Treatment of inflammatory conditions by delivery of interleukin-1 receptor antagonist fusion protein

ABSTRACT

The present invention provides, among other things, methods of treating post-cardiac injury syndrome (PCIS) or pericarditis, comprising a step of administering to a subject in need of treatment an interleukin-1 receptor-Fc fusion protein at a therapeutically effective dose and an administration interval for a treatment period sufficient to improve, stabilize or reduce one or more signs and symptoms of pericarditis relative to a control.

RELATED APPLICATIONS

This application is a Divisional Application of U.S. application Ser.No. 17/208,409, filed Mar. 22, 2021, which is a Divisional Applicationof U.S. application Ser. No. 16/143,391, filed Sep. 26, 2018, issued asU.S. Pat. No. 11,026,997, which claims priority to U.S. ProvisionalApplications Ser. No. 62/563,387, filed on Sep. 26, 2017; Ser. No.62/616,819, filed on Jan. 12, 2018; Ser. No. 62/625,075, filed on Feb.1, 2018; Ser. No. 62/639,425, filed on Mar. 6, 2018; Ser. No.62/654,291, filed on Apr. 6, 2018; Ser. No. 62/691,552, filed on Jun.28, 2018; and Ser. No. 62/716,331, filed on Aug. 8, 2018, thedisclosures of all of which are hereby incorporated by reference.

SEQUENCE LISTING

The present specification makes reference to a Sequence Listing(submitted electronically as a .txt file named “KPL-010US3_ST5” on Nov.15, 2021). The .txt file was generated on Nov. 14, 2021 and is bytes 24KB in size. The entire contents of the Sequence Listing are herebyincorporated by reference.

BACKGROUND

IL-1α and IL-1β provoke potent, pro-inflammatory events by engaging theIL-1α and IL-1β receptor. Following tissue insult, the release of IL-1αacts as the primary initiating signal to coordinate the mobilization ofimmune cells to the damaged area, while IL-1β is secreted mostly bymacrophages and is a prototypical cytokine of the canonicalinflammasome. IL-1α and IL-1β signaling results in a dramatic increasein the production of cytokines that orchestrate the proliferation andrecruitment of phagocytes to the site of damage, resulting ininflammation. Moreover, IL-1α and IL-1β signaling also affect otherimmune-system cells, such as T-cells and B-cells.

IL-1β's role in the inflammation process has been extensively studied,while in comparison, much is still unknown about the independentfunction of IL-1α in disease pathology. Despite driving similarimmunological outcomes, IL-1α and IL-1β differ substantially in theirexpression and regulation, and non-redundant roles for IL-1α and IL-1βhave been demonstrated in multiple inflammatory diseases. There aredisease states in which IL-1β inhibition alone does not appear to besufficient for disease remission in the absence of IL-1α inhibition.Published studies suggest certain autoinflammatory diseases may, infact, be pathologically driven primarily by IL-1α.

Post-cardiac injury syndrome (PCIS) is an aetiologic heterogeneous groupof autoimmune-mediated conditions of pericardial, epicardial, andmyocardial inflammation. Pericarditis is the inflammation of thepericardium, the thin, two-layered, fluid-filled, sac surrounding theheart. Pericarditis often causes chest pain and sometimes othersymptoms. The sharp chest pain associated with pericarditis occurs whenthe irritated layers of the pericardium rub against each other. Signsand symptoms of pericarditis may include some or all of the following:sharp, piercing chest pain over the center or left side of the chest,which is generally more intense when breathing in or reclining;shortness of breath when reclining; heart palpitations; low-grade fever;an overall sense of weakness, fatigue or feeling sick; cough; andabdominal or leg swelling.

Currently available treatments for pericarditis include medications toreduce the inflammation and swelling associated with pericarditis. Thesemedications include non-steroidal anti-inflammatory drugs, such asaspirin, ibuprofen or indomethacin; colchicine, which reducesinflammation; and corticosteroids, if a patient doesn't respond to painrelievers or colchicine or if a patient has current symptoms orpericarditis. Colchicine can reduce the duration of pericarditissymptoms and decrease the risk that the condition will recur, but themedication is not safe for patients with pre-existing health conditionslike liver or kidney disease or for patients taking certain medicationsand may cause side effects, including nausea and diarrhea, that can leadto discontinuation of treatment. Steroids are known to cause significantside effects, particularly with long-term use. Patients with refractorysymptoms can be particularly challenging to manage, and as a result,there is a significant and very long-standing need to identify newagents with favorable benefit to risk ratios that can be givensystemically to treat pericarditis.

SUMMARY OF THE INVENTION

The present invention provides, among other things, methods of treatingpost-cardiac injury syndromes (PCISs) and pericarditis with aninterleukin-1 receptor-Fc fusion protein. In particular, the presentinvention is based on the therapeutic efficacy observed in humanpericarditis patients, especially patients with recurrent pericarditis,after administrating a recombinant IL-1 receptor/IL-1 accessoryprotein-Fc fusion protein (e.g., IL-1 receptor-Fc fusion protein).Without wishing to be bound by any theory, it is contemplated that therecombinant IL-1-Fc fusion protein used in the present invention acts asa soluble decoy receptor binding IL-1α/IL-1β and prevents theirinteraction with the IL-1 cell surface receptor. As demonstrated in theExamples below, administration of such a recombinant IL-1 receptor-Fcfusion protein resulted in clinically significant reduction ofpericarditis associated inflammation and pain, and clinicallysignificant improvement in cardiac pathology. Moreover, the use of arecombinant IL-1 receptor-Fc fusion protein according to the presentinvention resulted in positive safety and tolerability profile. Thus,the present invention addresses the unmet need in pericarditis treatmentby providing a highly safe and efficacious drug for this disease.

In one aspect, the present invention provides a method of treatingpost-cardiac injury syndrome (PCIS) comprising a step of administeringto a subject in need of treatment an interleukin-1 receptor-Fc fusionprotein at a therapeutically effective dose and an administrationinterval for a treatment period sufficient to improve, stabilize orreduce one or more symptoms of PCIS relative to a control. In anotheraspect, the present invention provides methods of treating pericarditis,comprising a step of administering to a subject in need of treatment aninterleukin-1 receptor-Fc fusion protein at a therapeutically effectivedose and an administration interval for a treatment period sufficient toimprove, stabilize or reduce one or more symptoms of pericarditisrelative to a control. In one embodiment, the pericarditis is recurrentpericarditis. In another embodiment, the pericarditis is refractorypericarditis. In one embodiment, the pericarditis is idiopathicpericarditis. In one embodiment, the idiopathic pericarditis isrecurrent idiopathic pericarditis. In another embodiment, thepericarditis is non-idiopathic pericarditis, including, for example,pericarditis associated with a PCIS. In some embodiments, thepericarditis is recurrent non-idiopathic pericarditis. In someembodiments, the idiopathic pericarditis is refractory idiopathicpericarditis. In some embodiments, the pericarditis is refractorynon-idiopathic pericarditis.

In some embodiments, the PCIS is selected from myocardial infarctionpericarditis, post-myocardial infarction pericarditis,post-pericardiotomy syndrome (PPS) or post-traumatic pericarditis. Incertain embodiments, the post-myocardial infarction pericarditis isearly post-myocardial infarct-associated pericarditis (pericarditisepistenocardica) or late post-myocardial infarction pericarditis(Dressler's Syndrome). In other embodiments, the post-traumaticpericarditis is non-iatrogenic trauma or iatrogenic trauma. In oneembodiment, the idiopathic pericarditis is associated with Adult-OnsetStill's Disease. In one embodiment, the pericarditis is recurrent,non-idiopathic pericarditis.

In some embodiments, the subject in need of treatment has recurrentpericarditis. In some embodiments, the subject in need of treatment hasrecurrent idiopathic pericarditis. In some embodiments, the subject inneed of treatment has recurrent non-idiopathic pericarditis.

In one embodiment, the subject has refractory pericarditis. In oneembodiment, the subject has refractory idiopathic or non-idiopathicpericarditis.

In one embodiment, the subject has post-cardiac injury syndrome (PCIS).In certain embodiments, the subject has post-myocardial infarctionpericarditis, post-pericardiotomy syndrome (PPS) or post-traumaticpericarditis, early post-myocardial infarct-associated pericarditis(pericarditis epistenocardica) or late post-myocardial infarctionpericarditis (Dressler's Syndrome). In other embodiments, thepost-traumatic pericarditis is non-iatrogenic trauma or iatrogenictrauma. In one embodiment, the subject has pericarditis associated withAdult-Onset Still's Disease.

In one embodiment, the subject has pericarditis. In one embodiment, thesubject has pericarditis as a symptom, or associated with PCSI. In oneembodiment, the subject has recurrent or refractory pericarditis. In oneembodiment, the subject has idiopathic pericarditis. In one embodiment,the subject has recurrent idiopathic pericarditis.

In one embodiment, the step of administering comprises subcutaneousadministration. In one embodiment, the subcutaneous administration isthrough subcutaneous injection. In one embodiment, the step ofadministering comprises an initial loading dose, followed by at leastone maintenance dose. In one embodiment, the initial loading dose isgreater than the at least one maintenance dose. In one embodiment, theinitial loading dose is twofold greater in dosage than the dosage of theat least one maintenance dose. In one embodiment, the initial loadingdose is delivered as two injections of equal dosage. In one embodiment,the therapeutically effective dose comprises an initial loading dose ora maintenance dose. In one embodiment, the therapeutically effectivedose is equal to or greater than 320 mg. In one embodiment, thetherapeutically effective dose comprises an initial loading dose equalto or greater than 320 mg. In one embodiment, the initial loading doseis delivered as two injections of 160 mg. In one embodiment, thetherapeutically effective dose is equal to or greater than 160 mg. Inone embodiment, the therapeutically effective dose comprises amaintenance dose equal to or greater than 160 mg. In one embodiment, thetherapeutically effective dose comprises an initial loading dose equalto or greater than 160 mg. In one embodiment, the initial loading doseis delivered as two injections of 80 mg. In one embodiment, thetherapeutically effective dose is equal to or greater than 80 mg. In oneembodiment, the therapeutically effective dose comprises a maintenancedose equal to or greater than 80 mg.

In one embodiment, the therapeutically effective dose is equal to orgreater than 4 mg/kg. In one embodiment, the therapeutically effectivedose comprises an initial loading dose equal to or greater than 4 mg/kg.In a particular embodiment, the initial loading dose is equal to orgreater than 4.4 mg/kg. In some embodiments, the initial loading dose isdelivered as a single injection. In some embodiments, the initialloading dose is delivered as two injections of 2.2 mg/kg. In oneembodiment, the therapeutically effective dose is equal to or greaterthan 2 mg/kg. In another embodiment, the therapeutically effective dosecomprises a maintenance dose equal to or greater than 2 mg/kg. In aparticular embodiment, the maintenance dose is equal to or greater than2.2 mg/kg.

In one embodiment, the therapeutically effective dose is delivered as avolume of less than or equal to 2 mL.

In one embodiment, the administration interval is once every week. Inone embodiment, the administration interval is at least five days. Inone embodiment, the administration interval is once every two weeks. Inone embodiment, the administration interval is once every three weeks.In one embodiment, the administration interval is once every four weeks.In one embodiment, the administration interval is once every five weeks.

In one embodiment, the subject in need of treatment is 18 years of ageor older. In a particular embodiment, the initial loading dose isdelivered as two injections of 160 mg each and the maintenance dose isdelivered 160 mg per week to a subject 18 years of age or older. In someembodiments, a subject is re-administered a loading dose of 320 mg. Insome embodiments, a subject is administered double the quantity ofloading dose of 320 mg. In some embodiments, a subject is administeredabout 720 mg of IL-1 receptor-Fc fusion protein.

In another embodiment, the subject in need of treatment is younger than18 years of age. In one embodiment, the subject in need of treatment is6 to <18 years of age. In a particular embodiment, the initial loadingdose is delivered as two injections of 2.2 mg/kg each and themaintenance dose is delivered 2.2 mg/kg per week to a subject 6 to <18years of age.

In one embodiment, the one or more symptoms of pericarditis are assessedby a Numerical Rating Scale (NRS) for assessment of pericarditis pain.In one embodiment, the one or more signs of pericarditis are assessed byan echocardiogram. In one embodiment, the one or more signs ofpericarditis assessed by an echocardiogram comprise pericardialeffusion. In one embodiment, the one or more signs of pericarditis areassessed by an electrocardiogram (ECG). In one embodiment, the one ormore symptoms of pericarditis assessed by an ECG comprise widespreadST-elevation and/or PR depression. In one embodiment, the one or moresigns of pericarditis comprise fever and/or pericardial rub. In oneembodiment, the one or more signs of pericarditis are assessed bycardiac magnetic resonance imaging (MM). In one embodiment, the one ormore symptoms of pericarditis are assessed by measuring blood levels ofC-reactive protein (CRP). In one embodiment, measuring blood levels ofCRP comprises measuring blood levels of CRP at several time points afteran administering an initial loading dose of the interleukin-1receptor-Fc fusion protein, wherein a linear regression is performed todetermine the change of CRP levels from baseline, change of CRP levelsfrom baseline adjusted for placebo effect and/or the slope of bloodlevels of CRP over time. In some embodiments, change of blood CRP levelis not measured. In one embodiment, the one or more symptoms ofpericarditis are assessed by a Quality of Life Questionnaire. In oneembodiment, the administration of the interleukin-1 receptor-Fc fusionprotein results in a statistically-significant drop on a NumericalRating Scale (NRS) for assessment of pericarditis pain. In oneembodiment, the control is indicative of the one or more symptoms ofpericarditis in the subject before the treatment. In one embodiment, theone or more symptoms of pericarditis in the subject before the treatmentcomprise a CRP value greater than 1 mg/dL.

In one embodiment, the subject in need of treatment has had an indexepisode of pericarditis. As used herein, the term “index” is usedinterchangeably with “incident” and in each case represents the firstincident of pericarditis in the subject. In one embodiment, the indexepisode of pericarditis met at least two criteria for an acutepericarditis event, wherein the criteria comprise pericarditic chestpain, pericardial rubs, new widespread ST-segment elevation orPR-segment depression on ECG, and new or worsening pericardial effusion.In one embodiment, the subject in need of treatment has had at least onerecurrent episode of pericarditis. In one embodiment, the subject inneed of treatment has an ongoing symptomatic episode of pericarditis. Inone embodiment, the control is indicative of the one or more symptoms ofpericarditis in a control subject with the same disease status withouttreatment. In one embodiment, the control is indicative of the one ormore symptoms of pericarditis as determined by evaluating healthinformation from pericarditis patients over time, demonstrating thenatural progress of the condition, which can be obtained, for example,from a natural history study of pericarditis. In some embodiments, acontrol is indicative of the disease state when a subject having thedisease receives a standard of care therapy, in absence of IL-1receptor-Fc fusion protein administration.

In one embodiment, the administration results in no serious adverseevents in the subject. In one embodiment, the administration results inserious adverse events that are acceptable in view of the specifictreatment benefits. In one embodiment, the administration does notresult in an adverse effect selected from the group consisting ofinjection-site reaction, upper respiratory tract infection, headache,nausea, vomiting, diarrhea, sinusitis, arthralgia, flu-like symptoms,abdominal pain, pyrexia, nasopharyngitis, ischemic optic neuropathy andcombinations thereof.

In one embodiment, the interleukin-1 receptor-Fc fusion proteincomprises an amino acid sequence of SEQ ID NO: 1. In one embodiment, theinterleukin-1 receptor-Fc fusion protein comprises an amino acidsequence at least 90% identical to SEQ ID NO: 1. In one embodiment, theinterleukin-1 receptor-Fc fusion protein comprises CH1 and CH2 domainsderived from a human IgG1.

In one embodiment, the treatment allows for the withdrawal or weaning ofa concurrent therapy selected from the group consisting of NSAIDs,colchicine, corticosteroid and combinations thereof.

In one embodiment, the subject is diagnosed with recurrent or refractorypericarditis. In one embodiment, the subject is diagnosed withidiopathic pericarditis. In one embodiment, the subject is diagnosedwith recurrent idiopathic pericarditis. In one embodiment, the subjectis diagnosed with refractory idiopathic pericarditis. In one embodiment,the subject is diagnosed with non-idiopathic pericarditis. In oneembodiment, the subject is diagnosed with recurrent non-idiopathicpericarditis. In one embodiment, the subject is diagnosed withrefractory non-idiopathic pericarditis. In one embodiment, the subjectis diagnosed with post-cardiac injury syndrome (PCIS). In certainembodiments, the subject is diagnosed with post-myocardial infarctionpericarditis, post-pericardiotomy syndrome (PPS) or post-traumaticpericarditis. In certain embodiments, the post-myocardial infarctionpericarditis is early post-myocardial infarct-associated pericarditis(pericarditis epistenocardica) or late post-myocardial infarctionpericarditis (Dressler's Syndrome). In other embodiments, thepost-traumatic pericarditis is non-iatrogenic trauma or iatrogenictrauma. In one embodiment, the subject is diagnosed with Adult-OnsetStill's Disease.

In one embodiment, the interleukin-1 receptor-Fc fusion protein isrilonacept.

In one embodiment, the subject is colchicine-resistant,corticosteroid-dependent, corticosteroid-intolerant,corticosteroid-refractory and combinations thereof.

In one embodiment, the subject a symptomatic subject with pericarditiswith an elevated level of a marker of systemic inflammation, where theCRP level is ≥1 mg/dL; or, is a symptomatic subject with pericarditiswith non-elevated levels of an inflammatory marker and with pericardialinflammation present using an imaging technique; the subject beingNSAID-, corticosteroid- and/or colchicine-resistant or intolerant; or asubject with NSAID-, corticosteroid- and/or colchicine-dependentpericarditis but does not experience symptoms that would meet thediagnostic criteria for a flare of pericarditis; or a symptomaticsubject with PCIS with or without an elevated marker of systemicinflammation; where the subject is NSAID-, corticosteroid- and/orcolchicine-resistant or intolerant; and/or with NSAID, corticosteroid-and/or colchicine-dependent PCIS but does not experience symptoms thatwould meet the diagnostic criteria for PCIS, such as, for example,criteria for a flare of pericarditis.

In one embodiment, administration of the interleukin-1 receptor-Fcfusion protein results in a reduced CRP level selected from less thanabout 2 mg/dL, less than about 1.5 mg/dL, less than about 1 mg/dL, lessthan about 0.8 mg/dL, less than about 0.6 mg/dL, less than about 0.5mg/dL, less than about 0.4 mg/dL, less than about 0.3 mg/dL, less thanabout 0.2 mg/dL, or less than about 0.1 mg/dL in the subject. In someembodiments, the reduced CRP level is less than about 1 mg/dL. In someembodiments, the reduced CRP level ranges from about 0.3-1 mg/dL. Insome embodiments, the reduced CRP level is less than 0.3 mg/dL.

In one embodiment, the CRP level is reduced to less than 1 mg/dL within2 weeks, within 1 week, within 6 days, within 5 days, within 4 days,within 3 days, within 2 days, or within 1 day from the firstadministration of the interleukin-1 receptor-Fc fusion protein. In someembodiments, the CRP level is reduced to less than 1 mg/dL within 1 weekfrom the first administration of the interleukin-1 receptor-Fc fusionprotein. In some embodiments, the CRP level is maintained at less than 1mg/dL for more than about 2 weeks, more than about 4 weeks, more thanabout 1 month, more than about 2 months, more than about 3 months morethan about 4 months, more than about 5 months, more than about 6 months,more than about 7 months, more than about 8 months, more than about 10months, or more than about 1 year. In some embodiments, the CRP level ismaintained at less than 1 mg/dL for more than about 2 weeks, more thanabout 4 weeks, more than about 1 month, more than about 2 months, morethan about 3 months more than about 4 months, more than about 5 months,more than about 6 months, more than about 7 months, more than about 8months, more than about 10 months, or more than about 1 year, while thepatient continues to receive a therapeutic dose of interleukin-1receptor-Fc fusion protein at an administration interval and treatmentperiod according to the invention. In some embodiments, the CRP level ismaintained at less than 1 mg/dL for the above-indicated periods whilethe subject receives interleukin-1 receptor-Fc fusion protein in absenceof any concurrent therapy.

In some embodiments, the CRP level is reduced to less than 0.3 mg/dLwithin 3 weeks from the first administration of the interleukin-1receptor-Fc fusion protein. In some embodiments, the CRP level ismaintained at less than 0.3 mg/dL for more than about 1 week, more thanabout 2 weeks, more than about 3 weeks, more than about 1 month, morethan about 2 months, more than about 3 months more than about 4 months,more than about 5 months, more than about 6 months, more than about 8months, or more than about 1 year. In some embodiments, the CRP level ismaintained at less than 0.3 mg/dL for the above-indicated periodscontinues to receive a therapeutic dose of interleukin-1 receptor-Fcfusion protein at an administration interval and treatment periodaccording to the invention. In some embodiments, the CRP level ismaintained at less than 0.3 mg/dL for the above-indicated periods whilethe subject receives interleukin-1 receptor-Fc fusion protein in absenceof any concurrent therapy.

In one embodiment, administration of the interleukin-1 receptor-Fcfusion protein results in reduction of NRS score to 2 or less.

In one embodiment, the NRS score is reduced to 2 or less within 3 weeks,within 2 weeks or within 1 week from the first administration of theinterleukin-1 receptor-Fc fusion protein.

In some embodiments, the NRS score is maintained at 2 or less for morethan about 1 week, more than about 2 weeks, more than about 3 weeks,more than about 1 month, more than about 2 months, more than about 3months more than about 4 months, more than about 5 months, more thanabout 6 months, more than about 8 months, or more than about 1 year. Insome embodiments, the NRS level is maintained at 2 or less for theabove-indicated periods while the patient continues to receive atherapeutic dose of interleukin-1 receptor-Fc fusion protein at anadministration interval and treatment period according to the invention.In some embodiments, the NRS level is maintained at 2 or less for theabove-indicated periods while the subject receives interleukin-1receptor-Fc fusion protein in absence of any concurrent therapy.

In some embodiments, the interleukin-1 receptor-Fc fusion proteinresults in a reduced NRS score of 1 or less.

In some embodiments, the NRS score is reduced to 1 or less within 5weeks, within 4 weeks, within 3 weeks, within 2 weeks, or within 1 weekfrom the first administration of the interleukin-1 receptor-Fc fusionprotein at an administration interval and treatment period according tothe invention.

In some embodiments, the NRS score is maintained at 1 or less for morethan about 1 week, more than about 2 weeks, more than about 3 weeks,more than about 1 month, more than about 2 months, more than about 3months more than about 4 months, more than about 5 months, more thanabout 6 months, more than about 8 months, or more than about 1 year. Insome embodiments, the NRS level is maintained at 1 or less for theabove-indicated periods while the subject receives interleukin-1receptor-Fc fusion protein at an administration interval and treatmentperiod according to the invention. In some embodiments, the NRS level ismaintained at 1 or less for the above-indicated periods while thesubject receives interleukin-1 receptor-Fc fusion proteinin absence ofany concurrent therapy.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in decreased pericardiac effusion compared to acontrol. In some embodiments, a control is a baseline pericardiaceffusion level measured in the subject prior to the treatment. In someembodiments, a control is a pericardiac effusion level measured in asubject with comparable disease status but treated with a placebo. Insome embodiments, a control is a reference value indicative ofpericardiac effusion in a subject with comparable disease status withouttreatment. In some embodiments, a control is indicative of the diseasestate when a subject having the disease receives a standard of caretherapy, in absence of IL-1 receptor-Fc fusion protein administration.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in absence of pericardiac effusion.

In some embodiments, the decreased or absence of pericardiac effusion ismaintained for more than about 2 weeks, more than about 4 weeks, morethan about 1 month, more than about 2 months, more than about 3 monthsmore than about 4 months, more than about 5 months, more than about 6months, more than about 8 months, or more than about 1 year. In someembodiments, the decrease or absence of pericardiac effusion ismaintained for the above-indicated period, while the subject continuesto receive a therapeutic dose of interleukin-1 receptor-Fc fusionprotein at an administration interval and treatment period according tothe invention. In some embodiments, the decrease or absence ofpericardiac effusion is maintained for the above-indicated period, whilethe subject receives interleukin-1 receptor-Fc fusion protein in absenceof any concurrent therapy.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improved cardiac electrical conductivity inthe subject as determined by ECG as compared to a control. In someembodiments, the improved cardiac electrical conductivity as determinedby ECG comprises reduced ST-elevation and/or reduced SR depression.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in normalized cardiac electrical conductivity inthe subject as determined by an ECG evaluation.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improved cardiac effusion in the subject asdetermined by echocardiographic evaluation (ECHO) as compared to acontrol.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in normalized cardiac function in the subject asdetermined by ECHO evaluation.

In some embodiments, a control is a baseline cardiac parameter (e.g.,determined by ECG or ECHO, respectively) measured in the subject priorto the treatment. In some embodiments, a control is a cardiac parameter(e.g., determined by ECG or ECHO, respectively) measured in a subjectwith comparable disease status but treated with a placebo. In someembodiments, a control is a reference indicative of the cardiacparameter in a subject with comparable disease status withoutinterleukin-1 receptor-Fc fusion protein treatment. In some embodiments,a control is a reference indicative of the cardiac parameter in asubject with comparable disease status, receiving a standard of caretreatment, and without the interleukin-1 receptor-Fc fusion proteinadministration.

In some embodiments, the improved or normalized cardiac parameter ismaintained for more than about 2 weeks, more than about 4 weeks, morethan about 1 month, more than about 2 months, more than about 3 monthsmore than about 4 months, more than about 5 months, more than about 6months, more than about 8 months, or more than 1 year. In someembodiments, the normalized cardiac parameter is maintained for theabove-indicated period while the subject receives interleukin-1receptor-Fc fusion protein at an administration interval and treatmentperiod according to the invention. In some embodiments, the normalizedcardiac parameter is maintained for the above-indicated period while thesubject receives interleukin-1 receptor-Fc fusion protein in absence ofany concurrent therapy.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improved QoL scores in the subject as comparedto a control. In some embodiments, a control is baseline QoL scoresdetermined in the subject prior to the treatment. In some embodiments, acontrol is reference QoL scores in a subject with comparable diseasestatus but treated with a placebo. In some embodiments, a control is areference indicative of the QoL scores in a subject with comparabledisease status without treatment. In some embodiments, a control isindicative of the QoL when a subject having the disease receives astandard of care therapy, in absence of IL-1 receptor-Fc fusion proteinadministration.

In some embodiments, the improved QoL scores comprise one or moreassessments selected from: Patient Global Impression of PericarditisSeverity (PGIPS); Physician Global Assessment of Pericarditis Activity(PGA-PA); 36-Item Short Form Health Survey (SF-36); 5-Level EuroQoL-5D(EQ-5D-5L) and Insomnia severity Index (ISI).

In some embodiments, the improved QoL scores comprise a reduced ISIindicative of clinically insignificant insomnia having a score value ofless than 7 in the 5-point Likert scale.

In some embodiments, the improved QoL scores are maintained for morethan 2 weeks, more than 3 weeks, more than 1 month, more than 2 months,more than 3 months, more than 4 months, more than 5 months, more than 6months, more than 8 months, or more than 1 year from the date of firstadministration. In some embodiments, the improved QoL scores aremaintained for the above-indicated periods while the subject receivesinterleukin-1 receptor-Fc fusion protein. In some embodiments, theimproved QoL scores are maintained for the above-indicated periods whilethe subject receives interleukin-1 receptor-Fc fusion protein in absenceof any concurrent therapy.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in a period of recurrence-free survival of thesubject in absence of other standard of care (SOC) medicines. In someembodiments, the recurrence-free period is at least a month, at leastfive weeks, at least six weeks, at least seven weeks, at least eightweeks, at least three months, at least four months, at least fivemonths, at least six months, or at least one year.

In some embodiments, the treatment period with interleukin-1 receptor-Fcfusion protein lasts for 1 week. In some embodiments the treatmentperiod with interleukin-1 receptor-Fc fusion protein lasts for 2 weeks,3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks or 10weeks. In some embodiments, the treatment period lasts 2 months, 3months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10months, 11 months or 1 year. In some embodiments, the treatment periodlasts for more than 1 year. In some embodiments, the treatment periodencompasses an administration of a dose and a time interval inaccordance to the invention.

In some aspects, the invention provides a method of treatingpost-pericardiotomy syndrome (PPS), the method comprising a step ofadministering to a subject in need of treatment an interleukin-1receptor-Fc fusion protein at a therapeutically effective dose and anadministration interval for a treatment period sufficient to improve,stabilize or reduce one or more symptoms of post-pericardiotomypericarditis relative to a control.

In some embodiments, the invention provides a method of treatingpericarditis, PCIS or PPS by administering an interleukin-1 (IL-1)antagonistat a therapeutically effective dose and an administrationinterval for a treatment period sufficient to improve, stabilize orreduce one or more symptoms of post-pericardiotomy pericarditis relativeto a control. In some embodiments, the interleukin-1 antagonist is anIL-1α, IL-1β or IL-1 receptor binding protein (e.g., an anti-IL-1αantibody or a fragment thereof), a soluble receptor for interleukin-1,IL-1ra or an interleukin-1 receptor fusion protein.

It is to be understood that all embodiments as described above areapplicable to all aspects of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are for illustration purposes only not for limitation.

FIG. 1A-I depicts serum CRP levels and pain in NRS units in ninepatients, designated as Subjects A-I respectively after beingadministered 320 mg loading dose of interleukin-1 receptor-Fc fusionprotein at day 0, followed by 160 mg once a week. X-axis shows daysafter treatment. Subjects A-I were enrolled under Group 1. Therespective concurrent treatments and duration are designated graphicallybelow the X-axis.

FIG. 2A-B depicts serum CRP levels and pain in NRS units in a Subject Aand Subject B respectively after being administered 320 mg loading doseof interleukin-1 receptor-Fc fusion protein at day 0, followed by 160 mgonce a week. X-axis shows days after treatment. Subject A and Subject Bin this figure was enrolled under Group 2. The respective concurrenttreatments and duration are designated graphically below the X-axis.

FIG. 3A-C depicts serum CRP levels and pain in NRS units in Subjects A-Cafter being administered 320 mg loading dose of interleukin-1receptor-Fc fusion protein at day 0, followed by 160 mg once a week.X-axis shows days after treatment. Subjects A-C in this figure wereenrolled under Group 3. The respective concurrent treatments andduration are designated graphically below the X-axis.

FIG. 4 depicts a graphic representation of the study protocol for longterm efficacy of interleukin-1 receptor-Fc fusion protein in subjectswith recurrent pericarditis. CS=corticosteroid; EOS=end of study,LTE=Long Term Extension; NSAID=nonsteroidal anti-inflammatory drug;RI=run in, RW=randomized withdrawal, SC=subcutaneously, TP=treatmentperiod. a. The first dose given is a loading dose of IL1R-FcFP. In adultsubjects ≥18 years old, 320 mg is given as 2 SC doses of 160 mg. Inpaediatric subjects ≥12 and <18 years old, 4.4 mg/kg is given as 2 SCdoses of 2.2 mg/kg. After the loading dose, IL1R-FcFP will beadministered as a 160 mg (adults) or 2.2 mg/kg (paediatric subjects) SCdose once weekly. b. Subject's treatment duration will depend on whenthe subject is enrolled relative to the end of RW. c. The adult dose is160 mg SC once weekly. The paediatric dose is 2.2 mg/kg SC once weekly.Note: Figure is not drawn to scale.

FIG. 5 is a representative table of additional outcome measures, such aspresence of effusion, QoL and ECG changes, acquired from subjects inGroups 1-3 from the phase II clinical trial described in Example 2.

DEFINITIONS

In order for the present invention to be more readily understood,certain terms are first defined below. Additional definitions for thefollowing terms and other terms are set forth throughout thespecification. The publications and other reference materials referencedherein to describe the background of the invention and to provideadditional detail regarding its practice are hereby incorporated byreference.

Amino acid: As used herein, term “amino acid,” in its broadest sense,refers to any compound and/or substance that can be incorporated into apolypeptide chain. In some embodiments, an amino acid has the generalstructure H₂N—C(H)(R)—COOH. In some embodiments, an amino acid is anaturally occurring amino acid. In some embodiments, an amino acid is asynthetic amino acid; in some embodiments, an amino acid is a d-aminoacid; in some embodiments, an amino acid is an 1-amino acid. “Standardamino acid” refers to any of the twenty standard 1-amino acids commonlyfound in naturally occurring peptides. “Nonstandard amino acid” refersto any amino acid, other than the standard amino acids, regardless ofwhether it is prepared synthetically or obtained from a natural source.As used herein, “synthetic amino acid” encompasses chemically modifiedamino acids, including but not limited to salts, amino acid derivatives(such as amides), and/or substitutions. Amino acids, including carboxyl-and/or amino-terminal amino acids in peptides, can be modified bymethylation, amidation, acetylation, protecting groups, and/orsubstitution with other chemical groups that can change the peptide'scirculating half-life without adversely affecting their activity. Aminoacids may participate in a disulfide bond. Amino acids may comprise oneor posttranslational modifications, such as association with one or morechemical entities (e.g., methyl groups, acetate groups, acetyl groups,phosphate groups, formyl moieties, isoprenoid groups, sulfate groups,polyethylene glycol moieties, lipid moieties, carbohydrate moieties,biotin moieties, etc.). The term “amino acid” is used interchangeablywith “amino acid residue,” and may refer to a free amino acid and/or toan amino acid residue of a peptide. It will be apparent from the contextin which the term is used whether it refers to a free amino acid or aresidue of a peptide.

Amelioration: As used herein, the term “amelioration” is meant theprevention, reduction or palliation of a state, or improvement of thestate of a subject. Amelioration includes, but does not require completerecovery or complete prevention of a disease condition. In someembodiments, amelioration includes increasing levels of relevant proteinor its activity that is deficient in relevant disease tissues. In someembodiments, amelioration includes decreasing levels of relevant proteinor its activity that is pathologically elevated in relevant diseasetissues.

Approximately or about: As used herein, the term “approximately” or“about,” as applied to one or more values of interest, refers to a valuethat is similar to a stated reference value. In certain embodiments, theterm “approximately” or “about” refers to a range of values that fallwithin 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greaterthan or less than) of the stated reference value unless otherwise statedor otherwise evident from the context (except where such number wouldexceed 100% of a possible value).

Delivery: As used herein, the term “delivery” encompasses both local andsystemic delivery.

Half-life: As used herein, the term “half-life” is the time required fora quantity such as nucleic acid or protein concentration or activity tofall to half of its value as measured at the beginning of a time period.

Improve, increase, or reduce: As used herein, the terms “improve,”“increase” or “reduce,” or grammatical equivalents, indicate values thatare relative to a baseline measurement, such as a measurement in thesame individual prior to initiation of the treatment described herein,or a measurement in a control subject (or multiple control subject) inthe absence of the treatment described herein, e.g., a subject who isadministered a placebo. A “control subject” is a subject with the samedisease as the subject being treated, but who received no treatment, orwho received placebo.

Substantial identity: The phrase “substantial identity” is used hereinto refer to a comparison between amino acid or nucleic acid sequences.As will be appreciated by those of ordinary skill in the art, twosequences are generally considered to be “substantially identical” ifthey contain identical residues in corresponding positions. As is wellknown in this art, amino acid or nucleic acid sequences may be comparedusing any of a variety of algorithms, including those available incommercial computer programs such as BLAS TN for nucleotide sequencesand BLASTP, gapped BLAST, and PSI-BLAST for amino acid sequences.Exemplary such programs are described in Altschul, et al., Basic localalignment search tool, J Mol. Biol., 215(3): 403-410, 1990; Altschul, etal., Methods in Enzymology; Altschul et al., Nucleic Acids Res.25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guideto the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al.,(eds.), Bioinformatics Methods and Protocols (Methods in MolecularBiology, Vol. 132), Humana Press, 1999. In addition to identifyingidentical sequences, the programs mentioned above typically provide anindication of the degree of identity. In some embodiments, two sequencesare considered to be substantially identical if at least 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99% or more of their corresponding residues are identical over arelevant stretch of residues. In some embodiments, the relevant stretchis a complete sequence. In some embodiments, the relevant stretch is atleast 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400,425, 450, 475, 500 or more residues.

Suitable for subcutaneous delivery: As used herein, the phrase “suitablefor subcutaneous delivery” or “formulation for subcutaneous delivery” asit relates to the pharmaceutical compositions of the present inventiongenerally refers to the stability, viscosity, tolerability andsolubility properties of such compositions, as well as the ability ofsuch compositions to deliver an effective amount of antibody containedtherein to the targeted site of delivery.

Patient: As used herein, the term “patient” refers to any organism towhich a provided composition may be administered, e.g., forexperimental, diagnostic, prophylactic, cosmetic, and/or therapeuticpurposes. Typical patients include animals (e.g., mammals such as mice,rats, rabbits, non-human primates, and/or humans). In some embodiments,a patient is a human. A human includes pre- and post-natal forms.

Pharmaceutically acceptable: The term “pharmaceutically acceptable” asused herein, refers to substances that, within the scope of soundmedical judgment, are suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

Recurrence: As used herein, the term “recurrence” is defined as therecurrence of typical pericarditis pain associated with supportiveobjective evidence of pericarditis. Recurrence is often usedinterchangeably with “flare” and “relapse”. A pericarditis recurrence isusually indicated by any one or more of the following: an increase inthe CRP level of ≥1 mg/dl in peripheral blood; or an increase in pain,determined in an NRS scale of ≥4; or occurrence of pericardial effusion;a pericardial rub; or fever or any other symptomatic indication of thepericardial disease.

Subject: As used herein, the term “subject” refers to a human or anynon-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine,sheep, horse or primate). A human includes pre- and post-natal forms. Inmany embodiments, a subject is a human being. A subject can be apatient, which refers to a human presenting to a medical provider fordiagnosis or treatment of a disease. The term “subject” is used hereininterchangeably with “individual” or “patient.” A subject can beafflicted with or is susceptible to a disease or disorder but may or maynot display symptoms of the disease or disorder.

Substantially: As used herein, the term “substantially” refers to thequalitative condition of exhibiting total or near-total extent or degreeof a characteristic or property of interest. One of ordinary skill inthe biological arts will understand that biological and chemicalphenomena rarely, if ever, go to completion and/or proceed tocompleteness or achieve or avoid an absolute result. The term“substantially” is therefore used herein to capture the potential lackof completeness inherent in many biological and chemical phenomena.

Systemic distribution or delivery: As used herein, the terms “systemicdistribution,” “systemic delivery,” or grammatical equivalent, refer toa delivery or distribution mechanism or approach that affect the entirebody or an entire organism. Typically, systemic distribution or deliveryis accomplished via body's circulation system, e.g., blood stream.Compared to the definition of “local distribution or delivery.”

Target tissues: As used herein, the term “target tissues” refers to anytissue that is affected by a disease or disorder to be treated. In someembodiments, target tissues include those tissues that displaydisease-associated pathology, symptom, or feature.

Therapeutically effective amount: As used herein, the term“therapeutically effective amount” of a therapeutic agent means anamount that is sufficient, when administered to a subject suffering fromor susceptible to a disease, disorder, and/or condition, to treat,diagnose, prevent, and/or delay the onset of the symptom(s) of thedisease, disorder, and/or condition. It will be appreciated by those ofordinary skill in the art that a therapeutically effective amount istypically administered via a dosing regimen comprising at least one unitdose.

Treating: As used herein, the term “treat,” “treatment,” or “treating”refers to any method used to partially or completely alleviate,ameliorate, relieve, inhibit, prevent, delay onset of, reduce severityof and/or reduce incidence of one or more symptoms or features of aparticular disease, disorder, and/or condition. Treatment may beadministered to a subject who does not exhibit signs of a disease and/orexhibits only early signs of the disease for the purpose of decreasingthe risk of developing pathology associated with the disease.

DETAILED DESCRIPTION

The present invention provides, among other things, methods of treatingpericarditis comprising a step of administering to a subject in need oftreatment an interleukin-1 receptor-Fc fusion protein at atherapeutically effective dose and an administration interval for atreatment period sufficient to improve, stabilize or reduce one or moresymptoms of pericarditis relative to a control.

Various aspects of the invention are described in detail in thefollowing sections. The use of sections is not meant to limit theinvention. Each section can apply to any aspect of the invention. Inthis application, the use of “or” means “and/or” unless statedotherwise.

Post-Cardiac Injury Syndromes

Post-cardiac injury syndrome (PCIS) refers to an aetiologicheterogeneous group of autoimmune-mediated conditions of pericardial,epicardial, and myocardial inflammation. An invasive cardiac procedureor accidental trauma may give rise to myocardial, epicardial andpericardial damage. Inflammation of the epicardium and pericardium canlead to obvious symptoms such as pain, effusions, and fever. Patientssuffering from PCIS may present with chest pain, low grade fever anddyspnoea. Clinical symptoms include mild to moderate effusions both inthe pericardium and in the pleural space, and, in certain cases,pericardial friction rubs on auscultation. Laboratory analysis showssystemic inflammation with elevation of CRP and blood leucocytes.

In some cases, PCIS represents a leading cause of pericarditis. Theresulting tissue damage can lead to accumulation of debris and blood inthe pericardium. This results in immune responses, in which theinflammation persists in certain patients susceptible to this condition.

Symptom of PCISs include non-idiopathic pericarditis. As a group, PCISs,are an emerging cause of pericarditis and pericardial diseases,especially in developed countries and have been reported recently inabout 10% of unselected cases of acute pericarditis (Imazio, Int. J.Cardiol. 2013; 168:648-652). PCIS develops within days to months aftercardiac, pericardial injury or both and unlike post-myocardialinfarction syndrome, post-cardiac injury syndrome may acutely provoke agreater anti-heart antibody response (antisarcolemmal andantifibrillary). PCIS includes post-infarction pericarditis (Maisch etal, Eur Heart J. 2004; 25:587-610). Post-myocardial infarctionpericarditis includes two distinct forms; an “early” form (pericarditisepistenocardica) and a “delayed” form (Dressler's syndrome).Epistenocardiac pericarditis, caused by direct exudation, occurs in5-20% of transmural myocardial infarctions, but is clinically discoveredrarely, and Dressler's syndrome occurs from one week to several monthsafter clinical onset of myocardial infarction with symptoms andmanifestations similar to the post-cardiac injury syndrome (Maisch etal, 2004; 25:587-610). PCIS also includes post-pericardiotomy syndrome(PPS). PPS is a relatively frequent complication of cardiac surgery withan incidence of 10-40% in patients undergoing cardiac operation andoften occurs days to several weeks after cardiac surgery (Finkelstein etal, Herz. 2002; 27(8):791-794; Imazio et al, Eur. Heart. J. 2010;31(22):2749-2754; Imazio et al, JAMA. 2014; 312(10):1016-1023). PCISsalso include post-traumatic pericarditis, including non-iatrogenictrauma (i.e., following accidental blunt or penetrating thoracic trauma)and iatrogenic trauma (i.e., after percutaneous coronary or intracardiacinterventions, such as pacemaker lead insertion, radiofrequencyablation). Without wishing to be bound by any theory, PCISs are presumedto have an autoimmune pathogenesis triggered by an initial damage ofpericardial and/or pleural mesothelial cells, caused by the foregoingclinical conditions.

Pericarditis

Pericarditis is swelling and irritation of the pericardium, the thinsaclike membrane surrounding the heart. Pericarditis often causes chestpain and sometimes other symptoms. The sharp chest pain associated withpericarditis occurs when the irritated layers of the pericardium rubagainst each other. Signs and symptoms of pericarditis may include someor all of the following: sharp, piercing chest pain over the center orleft side of the chest, which is generally more intense when breathingin or reclining; shortness of breath when reclining; heart palpitations;low-grade fever; an overall sense of weakness, fatigue or feeling sick;cough; and abdominal or leg swelling.

Pericarditis accounts for 5% of emergency department visits for chestpain in the absence of myocardial infarction (Khandaker et al, Mayo ClinProc. 2010; 85:572-593). In 80% of cases in developed countries, thecause of pericarditis is either post viral or “idiopathic,” in that itcannot be attributed to a specific condition (Imazio et al, Circulation.2010; 121:916-928; Zayas et al, Am J Cardiol. 1995; 75:378-382).Diagnosis is based on the presence of typical chest pain (improved bysitting up and leaning forward) along with fever, pericardial frictionrub, electrocardiographic (ECG) changes, pericardial effusion, orelevated markers of inflammation (white blood cell [WBC] count,C-reactive protein [CRP], or erythrocyte sedimentation rate [ESR])(Imazio, Revista Espanola de Cardiologia. 2014; 67(5):345-348). TheEuropean Society of Cardiology (ESC) Guidelines for the Diagnosis andManagement of Pericardial Diseases define a pericarditis episode as thepresence of at least 2 of the 4 following criteria: pericarditic chestpain, pericardial rubs, new widespread ST-elevation or PR depression onECG, and pericardial effusion (new or worsening). Elevations of markersof inflammation (i.e., CRP, ESR, and WBD) or evidence of pericardialinflammation by an imaging technique (e.g., magnetic resonance imaging[MM]) are used as supportive findings (Adler et al, Eur Heart J. 2015Nov. 7; 36(42):2921-64). Recurrent pericarditis is a common complicationof acute pericarditis and affects 20-30% of patients (Imazio, RevistaEspanola de Cardiologia. 2014; 67(5):345-348). It is characterized bythe recurrence of signs and symptoms of pericarditis after asymptom-free interval of at least 4-6 weeks (Adler et al, Eur Heart J.2015 Nov. 7; 36(42):2921-64). The underlying pathogenesis of idiopathicrecurrent pericarditis (RIP) remains unclear, although immune-mediatedmechanisms are believed to play a key role in the pathogenesis (Imazioet al, American Journal of Cardiology, 2005; 96(5):736-739). A growingbody of evidence suggests that these immune responses consist of bothpathogenic autoimmune and auto-inflammatory processes (Cantarini et al,Autoimmunity Reviews 2015; 14:90-97; Doria et al, Autoimmunity Reviews2012; 12:22-30). The presence of pro-inflammatory cytokines in thepericardial fluid of RIP patients lends direct support to both anautoimmune and/or auto-inflammatory etiopathogenesis (Pankuwait et al,2000).

Currently available treatments for pericarditis include nonsteroidalanti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids(Lilly, 2013). Aspirin and other NSAIDs are the first-line approach.Several other NSAID commonly used are, ibuprofen, celecoxib, diclofenac,diflunisal, indomethacin, to name a few. Because high doses are oftenrequired, consideration has to be given to gastric protection therapy.Colchicine is another mainstay therapy for RIP and is commonly used withNSAIDs, but a subset of patients has refractory symptoms and significantgastrointestinal side effects, including severe diarrhea, leading todiscontinuation for intolerability. Glucocorticoids should be prescribedonly to patients with idiopathic pericarditis who are refractory orintolerant to treatment with NSAIDs plus colchicine, because of the sideeffects associated with long-term corticosteroid therapy and because ofa high rate of relapse when the corticosteroid is tapered or stopped(Maisch et al, Eur Heart J. 2004; 25:587-610; Imazio et al, Circulation.2005; 112:2012-2016; Lotrionte et al, Am Heart J. 2010; 160:662-670),particularly in the absence of colchicine treatment. Patients withrefractory symptoms can be particularly challenging to manage, andmultiple immunosuppressive medications have been used without consistentbenefit (Baskar et al, Cardiol Res Pract. 2016; 2016:7840724).

The cause of pericarditis is often hard to determine. In most cases,doctors either are unable to determine a cause (idiopathic) or suspect aviral infection. Although the underlying pathogenesis of idiopathicrecurrent pericarditis (RIP) (sometimes used interchangeably withrecurrent idiopathic pericarditis) remains unclear, immune-mediatedmechanisms are believed to play a key role in the pathogenesis (Imazioet al, 2005; 96(5):736-739). A growing body of evidence suggests thatthese immune responses consist of both pathogenic autoimmune andauto-inflammatory processes (Cantarini et al, Autoimmunity Reviews 2015;14:90-97; Doria et al, Autoimmunity Reviews 2012; 12:22-30). Thepresence of pro-inflammatory cytokines in the pericardial fluid of RIPpatients lends direct support to both an autoimmune and/orauto-inflammatory etiopathogenesis (Pankuwait et al, 2000).

Interleukin-1 (IL-1) is a key cytokine that drives the pathophysiologyof many inflammatory processes. It is implicated as a causative factorin various inflammatory human diseases. Although the pathogenicmechanism of auto-inflammatory disease is not completely understood,there is a growing body of evidence that IL-1 may be a primary driver ofthe symptomology and that targeting this cytokine may provide importantbenefits (Hoffman & Patel, Arthritis and Rheum. 2004 February; 50(2):345-349). In fact, a study of once-daily anakinra (KINERET®), arecombinant form of the human IL-1 receptor antagonist (IL-1RA), showedpromising effects in RIP patients when colchicine failed andcorticosteroid dependence (or intolerance) developed, with C-reactiveprotein (CRP) normalization within a mean of 7.1 days in 21consecutively treated patients (Brucato et al, JAMA. 2016 Nov. 8;316(18):1906-1912; Lazaros et al, J Cardiovasc Med 2016; 17(4):256-62).However, anakinra is a once-daily injection and is known to causeinjection site reaction among other adverse events. Thus, an IL-1antagonist, with an improved product profile that provides for one ormore of patient convenience; less treatment discomfort; effectivewithdrawal or weaning of NSAIDs, colchicine and/or corticosteroidtherapies; and a dosing frequency that facilitates a safe and effectiveweaning regimen prescribed by a physician, such as the interleukin-1receptor-Fc fusion proteins described herein, that antagonize binding ofboth IL-1α and IL-1β and prevents their interaction with IL-1 cellsurface receptors, provides a therapeutic opportunity for the treatmentof PCISs and pericarditis.

There are several different methods for assessing symptoms ofpericarditis. In one embodiment, one or more symptoms of pericarditisare assessed by a Numerical Rating Scale (NRS) for assessment ofpericarditis pain. NRS score is a self-reported assessment of the levelof pain a patient experiences in a scale of 0 to 10. In this 11-pointNRS scale, a score of 0 is interpreted as no pain, and a score of 10 isthe most severe pain. In one embodiment, one or more signs ofpericarditis are assessed by an echocardiogram. In one embodiment, theone or more signs of pericarditis assessed by an echocardiogram comprisepericardial effusion. In one embodiment, one or more signs ofpericarditis are assessed by an electrocardiogram (ECG). In oneembodiment, the one or more signs of pericarditis assessed by an ECGcomprise widespread ST-elevation and/or PR depression. In oneembodiment, one or more signs of pericarditis comprise fever and/orpericardial rub. In one embodiment, one or more signs and/or symptoms ofpericarditis are assessed by cardiac magnetic resonance imaging (MRI).In one embodiment, one or more signs of pericarditis are assessed bymeasuring blood levels of C-reactive protein (CRP). In one embodiment,measuring blood levels of CRP comprises measuring blood levels of CRP atseveral time points after an administering an initial loading dose ofthe interleukin-1 receptor-Fc fusion protein, wherein a linearregression is performed to determine the change of CRP levels frombaseline, change of CRP levels from baseline adjusted for placebo effectand/or the slope of blood levels of CRP over time. In some embodiments,a CRP level of greater than 1 mg/dL is considered positive forinflammation. In one embodiment, one or more symptoms of pericarditisare assessed by a Quality of Life Questionnaire.

Treatment

Among other things, methods according to the invention include treatingsubjects having PCIS or pericarditis by administering a therapeuticallyeffective amount of an IL-1 receptor-Fc fusion protein. In certaincases, the pericarditis may be associated with, or a symptom of a PCIS,while in other cases the cause of the pericarditis may be of uncertainor unknown origin (i.e., idiopathic). In some embodiments of theinvention, a PCIS or pericarditis is treated by administering to asubject in need of treatment an interleukin-1 receptor-Fc fusion proteinat a therapeutically effective dose and an administration interval for atreatment period sufficient to improve, stabilize or reduce one or moresigns and/or symptoms of pericarditis relative to a control. In someembodiments, the invention provides a method of treating subjects havingpost-pericardiotomy syndrome (PPS). Post-pericardiotomy is known tocause pericarditis. In some embodiments, PPS and/or PPS associatedpericarditis is treated by administering to a subject in need oftreatment an IL-1 antagonist, such as an interleukin-1 receptor-Fcfusion protein at a therapeutically effective dose and an administrationinterval for a treatment period sufficient to improve, stabilize orreduce one or more signs and/or symptoms of pericarditis relative to acontrol. In some embodiments, treatment of PPS with an interleukin-1receptor-Fc fusion protein at a therapeutically effective dose and anadministration interval for a period can result in prevention ofpericarditis, or delay in the appearance one or more signs and/orsymptoms of pericarditis. The terms, “treat” or “treatment,” as usedherein, refers to amelioration of one or more signs and/or symptomsassociated with the disease or disorder, prevention or delay of theonset of one or more signs and/or symptoms of the disease or disorder,and/or lessening of the severity or frequency of one or more signsand/or symptoms of the disease or disorder.

In some embodiments of the invention, the subject has one or more of thefollowing: recurrent or refractory pericarditis, idiopathicpericarditis, recurrent idiopathic pericarditis, refractory idiopathicpericarditis, non-idiopathic pericarditis, recurrent non-idiopathicpericarditis, refractory non-idiopathic pericarditis. In otherembodiments, the subject has a PCIS. In certain embodiments, a subjectwith PCIS has pericarditis. In various embodiments, the PCIS is, forexample, post-myocardial infarction pericarditis, PPS or post-traumaticpericarditis. In certain embodiments, the post-myocardial infarctionpericarditis is early post-myocardial infarct-associated pericarditis(pericarditis epistenocardica) or late post-myocardial infarctionpericarditis (Dressler's Syndrome). In other embodiments, thepost-traumatic pericarditis is non-iatrogenic trauma or iatrogenictrauma. In one embodiment, a subject with PPS, e.g., recurrent PPS, haspericarditis. In certain embodiments, the subject to be treated isselected from:

(i) a symptomatic subject with pericarditis with an elevated level of amarker of systemic inflammation (e.g., CRP≥1 mg/dL);

(ii) a symptomatic subject with pericarditis with non-elevated levels ofan inflammatory marker (e.g., CRP<1 mg/dL) and with pericardialinflammation present using an imaging technique (e.g., MRI);

(iii) the subject of (i) or (ii), where the subject is NSAID-,corticosteroid- and/or colchicine-resistant or intolerant;

(iv) a subject with NSAID, corticosteroid- and/or colchicine-dependentpericarditis not experiencing symptoms that would meet the diagnosticcriteria for a recurrence of pericarditis;

(v) a symptomatic subject with PCIS with or without an elevated markerof systemic inflammation (e.g., CRP≥1 mg/dL);

(vi) the subject of (v), where the subject is NSAID-, corticosteroid-and/or colchicine-resistant or intolerant; and

(vii) a subject with NSAID-, corticosteroid- and/or colchicine-dependentPCIS not experiencing symptoms that would meet the diagnostic criteriafor PCIS, such as, for example, criteria for a recurrence ofpericarditis.

In certain embodiments, the subject administered a therapeuticallyeffective amount of an IL-1 receptor-Fc fusion protein may be treatedwith concomitant medications, such as NSAIDs, colchicine orcorticosteroids, and combinations thereof, and optionally weaned fromone or more of such concomitant medications following treatment with theIL-1 receptor-Fc fusion protein. Typically, exemplary NSAIDs include butare not limited to ibuprufen, aspirin, indomethaxin, celecoxib,diclofenac. Exemplary corticosteroids include prednisone, cortisone,methyl prednisolone, and others.

In certain embodiments, the subject administered a therapeuticallyeffective amount of an IL-1 receptor-Fc fusion protein may also betreated with concomitant medications, such as NSAIDs, colchicine orcorticosteroids, and combinations thereof, and optionally weaned fromone or more of such concomitant medications following treatment with theIL-1 receptor-Fc fusion protein.

In some embodiments, the administration of an interleukin-1 receptor-Fcfusion protein results in a statistically-significant drop on aNumerical Rating Scale (NRS) for assessment of pericarditis pain. Insome embodiments, the administration of an interleukin-1 receptor-Fcfusion protein results in a statistically-significant change on acomposite endpoint that includes two or more of the following: NRS,blood levels of CRP, ECHO, pericardial rub, ECG, WBD, ESR and MRI.

In some embodiments, the step of administering comprises subcutaneousadministration. In some embodiments, subcutaneous administration isthrough subcutaneous injection. In some embodiments, subcutaneousadministration is through a subcutaneous pump. In some embodiments,subcutaneous injection of the interleukin-1 receptor-Fc fusion proteincan be performed in the upper arm, the anterior surface of the thigh,the lower portion of the abdomen, the upper back or the upper area ofthe buttock. In some embodiments, the site of injection is rotated.

In some embodiments, the effect of an interleukin-1 receptor-Fc fusionprotein on pericarditis is measured relative to a control. In someembodiments, a control is indicative of the one or more symptoms ofpericarditis in the subject before the treatment (also referred to as abaseline). In some embodiments, the control is indicative of the one ormore symptoms of pericarditis as determined by evaluating healthinformation from pericarditis patients over time, demonstrating thenatural progress of the condition, which can be obtained, for example,from a natural history study of pericarditis. In some embodiments, acontrol is indicative of the one or more symptoms of pericarditis in asubject with comparable disease status without treatment. In someembodiments, a control is indicative of the one or more symptoms ofpericarditis in a subject with comparable disease status, who is treatedwith a placebo. In some embodiments, a control is indicative of adisease state in a subject with comparable disease status, who receivesa standard of care therapy, in absence of IL-1 receptor-Fc fusionprotein administration.

In some embodiments, one or more symptoms of pericarditis in a subjectbefore treatment comprises a CRP value equal to or greater than 1 mg/dL.In some embodiments, a subject in need of treatment has had an indexepisode of pericarditis. In some embodiments, an index episode ofpericarditis met at least two criteria for an acute pericarditis event,wherein the criteria comprise pericarditic chest pain, pericardial rubs,new widespread ST-segment elevation or PR-segment depression on ECG, andnew or worsening pericardial effusion. In some embodiments, a subject inneed of treatment has had at least one recurrent episode ofpericarditis. In some embodiments, a subject in need of treatment hashad at least two recurrent episodes of pericarditis. In someembodiments, a subject in need of treatment has had at least threerecurrent episodes of pericarditis. In some embodiments, a recurrentepisode is defined as at least 1 day with pericarditis pain withpericarditis pain measurement ≥4 on the 11-point Numerical Rating Scale(NRS) and/or C-reactive protein (CRP) level ≥1 mg/dL. In someembodiments, pericarditis pain ≥4 and CRP≥1 mg/dL are present on thesame day. In some embodiments, pericarditis pain ≥4 and CRP≥1 mg/dL arenot present on the same day. In some embodiments, a subject beingtreated has at least one recurrent episode within 7 days prior to firstadministration. In some embodiments, a subject in need of treatment hasan ongoing symptomatic episode of pericarditis.

Dosage

A therapeutically effective dose of an interleukin-1 receptor-Fc fusionprotein for treating pericarditis can occur at various dosages. In someembodiments of the invention, a therapeutically effective dose is equalto or greater than 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg,160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg,340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg,520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg,700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg,880 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, or 1000 mg.

In some embodiments, a therapeutically effective dose is approximately20-800 mg, approximately 40-700 mg, approximately 60-600 mg,approximately 80-500 mg, approximately 100-400 mg, or approximately80-400 mg, 100-400 mg, 120-400 mg, approximately 140-400 mg,approximately 160-400 mg, approximately 180-400 mg, approximately200-400 mg, approximately 220-400 mg, approximately 240-400 mg,approximately 260-400 mg, approximately 280-400 mg, approximately300-400 mg, approximately 320-400 mg, approximately 340-400 mg,approximately 360-400 mg, approximately 380-400 mg, approximately 20-380mg, approximately 20-360 mg, approximately 20-340 mg, approximately20-320 mg, approximately 20-300 mg, approximately 20-280 mg,approximately 20-260 mg, approximately 20-240 mg, approximately 20-220mg, approximately 20-200 mg, approximately 20-180 mg, approximately20-160 mg, approximately 20-140 mg, approximately 20-120 mg,approximately 20-100 mg, approximately 20-80 mg, approximately 20-60 mg,or approximately 20-40 mg. In one embodiment, a therapeuticallyeffective dose is approximately 80-160 mg.

In some embodiments, a therapeutically effective dose is equal to orgreater than 320 mg/mL. In some embodiments, a therapeutically effectivedose comprises an initial loading dose equal to or greater than 320 mg.In some embodiments, the initial loading dose is delivered as twoinjections of 160 mg. In some embodiments, a therapeutically effectivedose is equal to or greater than 160 mg. In some embodiments, atherapeutically effective dose comprises a maintenance dose equal to orgreater than 160 mg. In some embodiments, a therapeutically effectivedose comprises an initial loading dose equal to or greater than 160 mg.In some embodiments, the initial loading dose is delivered as twoinjections of 80 mg. In some embodiments, a therapeutically effectivedose is equal to or greater than 80 mg. In some embodiments, atherapeutically effective dose comprises a maintenance dose equal to orgreater than 80 mg.

In some embodiments, a therapeutically effective dose is delivered as avolume of less than or equal to 2.0 mL for each subcutaneous injection.In some embodiments, a therapeutically effective dose is delivered as avolume of less than or equal to 1.8 mL. In some embodiments, atherapeutically effective dose is delivered as a volume of less than orequal to 1.6 mL. In some embodiments, a therapeutically effective doseis delivered as a volume of less than or equal to 1.4 mL. In someembodiments, a therapeutically effective dose is delivered as a volumeof less than or equal to 1.2 mL. In some embodiments, a therapeuticallyeffective dose is delivered as a volume of less than or equal to 1.0 mL.In some embodiments, a therapeutically effective dose is delivered as avolume of less than or equal to 0.8 mL. In some embodiments, atherapeutically effective dose is delivered as a volume of less than orequal to 0.6 mL.

In one embodiment, the therapeutically effective dose is equal to orgreater than 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/mg, 4 mg/kg, 5mg/kg, 6, mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg or 10 mg/kg. In oneembodiment, the therapeutically effective dose is approximately 0.1-10mg/kg, approximately 0.5-10 mg/kg, approximately 1-10 mg/kg,approximately 2-10 mg/kg, approximately 3-10 mg/kg, approximately 4-10mg/kg, approximately 5-10 mg/kg, approximately 6-10 mg/kg, approximately7-10 mg/kg, approximately 8-10 mg/kg, approximately 9-10 mg/kg,approximately 0.1-10 mg/kg, approximately 0.1-9 mg/kg, approximately0.1-8 mg/kg, approximately 0.1-7 mg/kg, approximately 0.1-6 mg/kg,approximately 0.1-5 mg/kg, approximately 0.1-4 mg/kg, approximately0.1-3 mg/kg, approximately 0.1-2 mg/kg, approximately 0.1-1 mg/kg,approximately 0.1-0.5 mg/kg.

In some embodiments, a therapeutically effective dose for a pediatricsubject (e.g., aged 2 to 17 years, aged 6 to <18 years) comprises aninitial loading dose of approximately 4 mg/kg, (e.g., 4.0 mg/kg, 4.1mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, or 4.5 mg/kg), up to a maximumof approximately 320 mg, delivered, for example, as one or twosubcutaneous injections with a maximum single-injection volume of 2 mL.In some embodiments, the initial loading dose described herein (e.g.,4.4 mg/kg) is delivered as two injections of equal dose amount (e.g., 2injections of 2.2 mg/kg). In some embodiments, a therapeuticallyeffective dose for a pediatric subject (e.g., aged 2 to 17 years, aged 6to <18 years) comprises a maintenance dose of approximately 2 mg/kg(e.g., 2.0 mg/kg 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg 2.4 mg/kg or 2.5mg/kg), up to a maximum of approximately 160 mg, administered, forexample, as a single subcutaneous injection, up to 2 mL in volume. Insome embodiments, the therapeutically dose for a pediatric subjectcomprises a maintenance dose of approximately 1.5 mg/kg to 2.5 mg/kg perweek, or 1.8 mg/kg to 2.4 mg/kg per week, or 2 mg/kg to 2.2 mg/kg perweek.

In some embodiments, administering comprises an initial loading dose,followed by at least one maintenance dose. In some embodiments, multiplemaintenance doses are administered following the initial loading dose.Typically, the maintenance dose is administered periodically (e.g.,weekly, once every two weeks, once every three weeks, once every fourweeks, monthly, once every five weeks). In some embodiments, the initialloading dose is greater than the at least one maintenance dose. In someembodiments, the initial loading dose is at least one-fold, two-fold,three-fold, four-fold or five-fold greater in dosage than the dosage ofthe at least one maintenance dose. In some embodiments, the initialloading dose is two-fold greater in dosage than the dosage of the atleast one maintenance dose.

Administration Interval

An administration interval of an interleukin-1 receptor-Fc fusionprotein in the treatment of pericarditis can occur at various durations.In some embodiments, the administration interval is every other day. Insome embodiments, the administration interval is multiple times a week.In some embodiments, the administration interval is at least five days.In some embodiments, the administration interval is once every week. Insome embodiments, the administration interval is once every two weeks.In some embodiments, the administration interval is once every threeweeks. In some embodiments, the administration interval is once everyfour weeks. In some embodiments, the administration interval is onceevery five weeks.

Treatment Period

A treatment period of pericarditis with an interleukin-1 receptor-Fcfusion protein can vary in duration. In some embodiments, the treatmentperiod is 1 week. In some embodiments, the treatment period withinterleukin-1 receptor-Fc fusion protein lasts for more than 1 week. Insome embodiments the treatment period with interleukin-1 receptor-Fcfusion protein lasts for 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7weeks, 8 weeks, 9 weeks or 10 weeks. In some embodiments, the treatmentperiod lasts 1 month, 2 months, 3 months, 4 months, 5 months, 6 months,7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13months, 14 months, 15 months, 16 months, 17 months or 18 months. In someembodiments, the treatment period lasts for more than 18 months. In someembodiments, the treatment period lasts for 2 years. The treatmentperiod encompasses administering the interleukin-1 receptor-Fc fusionprotein at a dose and a time interval in accordance to the invention.

In some embodiments, the treatment period is at least one month. In someembodiments, the treatment period is at least two months. In someembodiments, the treatment period is at least three months. In someembodiments, the treatment period is at least six months. In someembodiments, the treatment period is at least nine months. In someembodiments, the treatment period is at least one year. In someembodiments, the treatment period is at least two years. In someembodiments, the treatment period continues throughout the subject'slife.

Pharmacokinetics and Pharmacodynamics

Evaluation of interleukin-1 receptor-Fc fusion proteinconcentration-time profiles in serum of subjects with pericarditis maybe evaluated directly by measuring systemic serum interleukin-1receptor-Fc fusion protein concentration-time profiles. Typically,interleukin-1 receptor-Fc fusion protein pharmacokinetic andpharmacodynamic profiles are evaluated by sampling the blood of treatedsubjects periodically. The following standard abbreviations are used torepresent the associated pharmacokinetic parameters.

C_(max) maximum concentration

t_(max) time to maximum concentration

AUC_(0-t) area under the concentration-time curve (AUC) from time zeroto the last measurable concentration, calculated using the lineartrapezoidal rule for increasing concentrations and the logarithmic rulefor decreasing concentrations

AUC_(0-∞) AUC from time zero to infinity calculated using the formula:

${AUC}_{0 - \infty} = {{AUC}_{0 - t} + \frac{C_{t}}{\lambda_{z}}}$where C_(t) is the last measurable concentration and λ_(Z) is theapparent terminal elimination rate constant

λ_(Z) apparent terminal elimination rate constant, where λ_(Z) is themagnitude of the slope of the linear regression of the log concentrationversus time profile during the terminal phase

t_(1/2) apparent terminal elimination half-life (whenever possible),where t_(1/2)=natural log (ln)(2)/λ_(Z)

CL clearance

Vd volume of distribution (IV doses only)

Vd/F apparent volume of distribution (SC doses only)

Typically, actual blood sample collection times relative to the start ofinterleukin-1 receptor-Fc fusion protein administration are used in PKanalysis. For example, blood samples are typically collected, forexample, within 15 or 30 minutes prior to interleukin-1 receptor-Fcfusion protein administration (pre-injection baseline or time 0) and atperiodic intervals following administration, e.g., hours 1, 4, 8 or 12,or days 1 (24 hours), 2, 3, 4, 5, 6, 7, 10, 14, 17, 21, 24, 28, 31, 38,45, 52, 60, 70 or 90 days, following administration. In someembodiments, the blood samples are collected prior to an administrationtimepoint.

Various methods may be used to measure interleukin-1 receptor-Fc fusionprotein concentration in serum. As a non-limiting example, enzyme-linkedimmunosorbent assay (ELISA) methods are used.

Pharmacokinetic parameters may be evaluated at any stage during thetreatment, for example, at day 1, day 2, day 3, day 4, day 5, day 6,week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9,week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17,week 18, week 19, week 20, week 21, week 22, week 23, week 24, or later.In some embodiments, pharmacokinetic parameters may be evaluated atmonth 1, month 2, month 3, month 4, month 5, month 6, month 7, month 8,month 9, month 10, month 11, month 12, month 13, month 14, month 15,month 16, month 17, month 18, month 19, month 20, month 21, month 22,month 23, month 24, or later during the treatment.

Effectiveness Assessment

In some embodiments, the effectiveness of the treatment usinginterleukin-1 receptor-Fc fusion protein is determined by measuringinflammation, such as measuring the CRP level in peripheral blood. Insome embodiments administration of the interleukin-1 receptor-Fc fusionprotein results in a reduction of the CRP level compared to a scoreobserved prior to the administration. In some embodiments, the CRP levelis reduced to 2 mg/dL or less, 1.5 mg/dL or less, 1 mg/dL or less, 0.8mg/dL or less, 0.6 mg/dL or less, 0.5 mg/dL or less, 0.4 mg/dL or less,0.3 mg/dL or less, 0.2 mg/dL or less, 0.1 mg/dL or less in the subject.In some embodiments the reduction of CRP level is observed within 2weeks from the first administration. In some embodiments, the CRP levelis maintained at 2 mg/dL or less for longer than 2 weeks. In someembodiments, the CRP level is maintained at 2 mg/dL or less for longerthan 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7months, 8 months, 9 months, 10 months, 11 months or for longer than 1year. In some embodiments, the CRP level is maintained at 1 mg/dL orless for longer than 1 month, 2 months, 3 months, 4 months, 5 months, 6months, 7 months, 8 months, 9 months, 10 months, 11 months or for longerthan 1 year. In some embodiments, the CRP level is maintained at 1 mg/dLor less for the indicated period, while the patient continues to receivea therapeutic dose of interleukin-1 receptor-Fc fusion protein. In someembodiments, the CRP level is maintained at less than 1 mg/dL for theabove-indicated periods while the subject receives interleukin-1receptor-Fc fusion protein in absence of any concurrent therapy.

In some embodiments, the effectiveness of the treatment usinginterleukin-1 receptor-Fc fusion protein is determined by assessment ofpain in the subject, such as by determination of 11-point NRS score. Insome embodiments administration of the interleukin-1 receptor-Fc fusionprotein results in a reduction of the NRS score compared to a scoreobserved prior to administration. In some embodiments, an NRS score of 3or less is interpreted as mild to no pain. In some embodiments, areduction in NRS score to a value of 2 or less after administration ofthe interleukin-1 receptor-Fc fusion protein from a higher scoreobserved prior to the administration is considered an improvement of thedisease in the patient. In some embodiments the NRS score is reduced to2 or less within 2 weeks of the first administration. In someembodiments the NRS score is reduced to 1 or less. In some embodiments,the NRS score is maintained at 2 or less for longer than 2 weeks, 1month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 11 months or for longer than 1 year. Insome embodiments, the subject remains pain free for the duration of theextension period of the study. In some embodiments, the NRS score ismaintained at 2 or less for while the patient continues to receive atherapeutic dose of interleukin-1 receptor-Fc fusion protein at anadministration interval and treatment period according to the invention.In some embodiments, the NRS score is maintained at 2 or less for whilethe patient continues to receive a therapeutic dose of interleukin-1receptor-Fc fusion protein in absence of any concurrent therapy.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improved cardiac function, such as decreasedor ameliorated pericardiac effusion, compared to a control. Pericardialeffusion (also known as “fluid around the heart”) is an abnormalaccumulation of fluid in the pericardial cavity that is indicative ofinflammation, which leads to an increased intrapericardial pressure andcan negatively affect heart function. Cardiac health parameters,particularly pericardiac effusion, may be evaluated by echocardiography(ECHO), cardiac magnetic resonance imaging (MRI), and/or CT scanning. Insome embodiments, administration of the interleukin-1 receptor-Fc fusionprotein results in a decrease, absence or amelioration of pericardiaceffusion.

A control is a reference cardiac parameter such as a referencepericardiac effusion level measured in a subject with comparable diseasestatus but without treatment. For example, a control may be a baselinecardiac function such as a baseline pericardiac effusion measured in thesubject being treated prior to the treatment. A control may also be areference cardiac parameter such as a reference pericardiac effusionlevel measured in a subject with comparable disease status but treatedwith a placebo. In some embodiments, a control may be a reference valueor graph indicative of cardiac parameters such as pericardiac effusionin a subject with comparable disease status without treatment based onhistorical data. In some embodiments, a control may be a reference valueor graph indicative of a cardiac parameter such as pericardiac effusionin a subject with comparable disease status who receives a standard ofcare therapy, in absence of IL-1 receptor-Fc fusion proteinadministration.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improvement of cardiac parameters as indicatedby ECG measurements. A reduction in the ST elevation and/or reduction inthe depression after administration of the interleukin-1 receptor-Fcfusion protein is considered an improvement in the cardiac parameter.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improvement of cardiac effusion as determinedby echocardiography (ECHO).

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improvement of cardiac parameters asdetermined by CT scanning.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improvement of cardiac parameters asdetermined by cardiac magnetic resonance imaging (MM).

In some embodiments, administration of the interleukin-1 receptor-Fcfusion results in successful taper of steroids and other concurrenttherapies, while the subject continues to receive interleukin-1receptor-Fc fusion protein at an administration interval and treatmentperiod according to the invention. In some embodiments, administrationof the interleukin-1 receptor-Fc fusion protein results in weaning thesubject of steroids and/or other concurrent therapies starting at about4 weeks, or 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks or 24weeks after first administration, while the subject continues to receiveinterleukin-1 receptor-Fc fusion protein at an administration intervaland treatment period according to the invention. In some embodiments,administration of the interleukin-1 receptor-Fc fusion results in asuccessful taper of steroids and/or other concurrent therapies whichlasts for at least two weeks. In some embodiments, administration of theinterleukin-1 receptor-Fc fusion results in a successful taper ofsteroids and other concurrent therapies that lasts for at least threeweeks. In some embodiments, administration of the interleukin-1receptor-Fc fusion results in a successful taper of steroids and otherconcurrent therapies that lasts for at least four weeks. In someembodiments, administration of the interleukin-1 receptor-Fc fusionresults in a successful taper of steroids and other concurrent therapiesthat lasts for at least five weeks. In some embodiments, administrationof the interleukin-1 receptor-Fc fusion results in a successful taper ofsteroids and other concurrent therapies that lasts for at least sixweeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks,twelve weeks, thirteen weeks, fourteen weeks, fifteen weeks, sixteenweeks, seventeen weeks, eighteen weeks, nineteen weeks, twenty weeks,twenty one weeks, twenty two weeks, twenty three weeks, or twenty fourweeks. In some embodiments, administration of the interleukin-1receptor-Fc fusion results in a successful taper of steroids and otherconcurrent therapies that lasts for at least 6 months, 7 months, 8months, 9 months, 10 months, 11 months, or 1 year. In some embodiments,administration of the interleukin-1 receptor-Fc fusion results in asuccessful taper of steroids and other concurrent therapies for morethan 1 year. In some embodiments, administration of the interleukin-1receptor-Fc fusion results in the subject being free of steroids andother concurrent therapies for greater than 1 year. In some embodiments,the subject continues to receive interleukin-1 receptor-Fc fusionprotein administration at a therapeutic dose and administration intervalin accordance to the invention. In some embodiments, the subjectcontinues to receive interleukin-1 receptor-Fc fusion proteinadministration without any concurrent therapy.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in improvement of QoL scores. Typically, QoLscores comprise one or more assessments selected from: Patient GlobalImpression of Pericarditis Severity (PGIPS); Physician Global Assessmentof Pericarditis Activity (PGA-PA); 36-Item Short Form Health Survey(SF-36); 5-Level EuroQoL-5D (EQ-5D-5L) and Insomnia severity Index(ISI).

In some embodiments, the effectiveness of treatment using aninterleukin-1 receptor-Fc fusion protein is determined by Patient GlobalImpression of Pericarditis Severity (PGIPS), and/or Physician GlobalAssessment of Pericarditis Activity (PGA-PA). The PGIPS is a single-itempatient reported outcome (PRO) measure that assesses the subject'simpression of overall severity of pericarditis symptoms at the time thequestionnaire is administered, using a 7-point rating scale ranging fromabsent (no recurrent pericarditis symptoms) to very severe (recurrentpericarditis symptoms cannot be ignored). The PGA-PA is a single-itemclinician-reported outcome measure that investigators use to rate theirimpression of the patient's overall pericarditis disease activity at thetime the assessment is completed, using a 7-point rating scale rangingfrom absent to very severe. In some embodiments, administration of theinterleukin-1 receptor-Fc fusion protein results in an improved PGIPSand/or PGA-PA compared to a control.

In some embodiments, at least 50% of the subjects undergoing treatmentwith interleukin-1 receptor-Fc fusion protein report an absence orminimal pericarditis symptoms as determined by PGIPS. In someembodiments, at least 75% of the subjects undergoing treatment withinterleukin-1 receptor-Fc fusion protein report an absence or minimalpericarditis symptoms as determined by PGIPS. In some embodiments, atleast 80% of the subjects undergoing treatment with interleukin-1receptor-Fc fusion protein report an absence or minimal pericarditissymptoms as determined by PGIPS. In some embodiments, at least 90% ofthe subjects undergoing treatment with interleukin-1 receptor-Fc fusionprotein report an absence or minimal pericarditis symptoms as determinedby PGIPS. In some embodiments, at least 95% of the subjects undergoingtreatment with interleukin-1 receptor-Fc fusion protein report anabsence or minimal pericarditis symptoms as determined by PGIPS. In someembodiments, 97%, 98%, 99% or 100% of the subjects undergoing treatmentwith interleukin-1 receptor-Fc fusion protein report an absence orminimal pericarditis symptoms as determined by PGIPS.

In some embodiments, at least 50% of the subjects receivinginterleukin-1 receptor-Fc fusion protein show an absence or minimalpericarditis symptoms as determined by PGA-PA. In some embodiments, atleast 75% of the subjects undergoing treatment with interleukin-1receptor-Fc fusion protein show an absence or minimal pericarditissymptoms as determined by PGA-PA. In some embodiments, at least 80% ofthe subjects undergoing treatment with interleukin-1 receptor-Fc fusionprotein show an absence or minimal pericarditis symptoms as determinedby PGA-PA. In some embodiments, at least 90% of the subjects undergoingtreatment with interleukin-1 receptor-Fc fusion protein show an absenceor minimal pericarditis symptoms as determined by PGA-PA. In someembodiments, at least 95% of the subjects undergoing treatment withinterleukin-1 receptor-Fc fusion protein show an absence or minimalpericarditis symptoms as determined by PGA-PA. In some embodiments, 96%,97%, 98%, 99% or 100% of the subjects undergoing treatment withinterleukin-1 receptor-Fc fusion protein show an absence or minimalpericarditis symptoms as determined by PGA-PA.

In some embodiments, the effectiveness of the treatment usinginterleukin-1 receptor-Fc fusion protein is determined by a 5-LevelEuroQoL-5D (EQ-5D-5L)(additional information in: www.euroqol.org). TheEQ-5D-5L is a standardized instrument developed by the EuroQol Group asa measure of health-related quality of life that can be used inassessing a wide range of health conditions and treatments. The EQ-5D-5Lincludes a descriptive system and the EQ VAS. The descriptive systemcomprises 5 dimensions: mobility, self-care, usual activities,pain/discomfort and anxiety/depression. The rating scale records thesubject's self-rated health on a vertical Visual Analog Scale (VAS). Thescores on these 5 dimensions can be presented as a health profile or canbe converted to a single summary index number (utility) reflectingpreferability compared to other health profiles(euroqol.org/eq-5d-instruments).

In some embodiments, the EQ-5D-5L is collected in subjects ≥18 years orolder.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion protein results in an improved EQ-5D-5L. In some embodiments, atleast 50% of the subjects receiving interleukin-1 receptor-Fc fusionprotein show a clinical relevant improved EQ-5D-5L score. In someembodiments, at least 75% of the subjects undergoing treatment withinterleukin-1 receptor-Fc fusion protein show a clinical relevantimproved EQ-5D-5L score. In some embodiments, at least 80% of thesubjects undergoing treatment with interleukin-1 receptor-Fc fusionprotein show a clinical relevant improved EQ-5D-5L score. In someembodiments, at least 90% of the subjects undergoing treatment withinterleukin-1 receptor-Fc fusion protein show a clinical relevantimproved EQ-5D-5L score. In some embodiments, at least 95% of thesubjects undergoing treatment with interleukin-1 receptor-Fc fusionprotein show a clinical relevant improved EQ-5D-5L score. In someembodiments, 96%, 97%, 98%, 99% or 100% of the subjects undergoingtreatment with interleukin-1 receptor-Fc fusion protein a clinicalrelevant improved EQ-5D-5L score.

In some embodiments, a control for a QoL measurements indicated in thepreceding sections, is a baseline QoL scores determined in the subjectprior to the treatment. In some embodiments, a control is reference QoLscores in a subject with comparable disease status but treated with aplacebo. In some embodiments, a control is a reference indicative of QoLscores in a subject with comparable disease status without treatment. Insome embodiments, a control is indicative of the QoL when a subjecthaving the disease receives a standard of care therapy, in absence ofIL-1 receptor-Fc fusion protein administration.

In some embodiments, administration of the interleukin-1 receptor-Fcfusion results in an improved Insomnia Severity Index (ISI). The ISI isa 7-item self-report questionnaire assessing the nature, severity, andimpact of insomnia. The usual recall period is the “last 2 weeks” andthe dimensions evaluated are severity of sleep onset, sleep maintenance,early morning awakening problems, sleep dissatisfaction, interference ofsleep difficulties with daytime functioning, noticeability of sleepproblems by others, and distress caused by the sleep difficulties. A5-point Likert scale is used to rate each item (e.g., 0=no problem;4=very severe problem), yielding a total score ranging from 0 to 28. Thetotal score is interpreted as follows: no clinically significantinsomnia (0-7); subthreshold insomnia (8-14); clinical (moderate)insomnia (15-21); and clinical (severe) insomnia (22-28) (Morin et al.,Sleep. 2011; 34(5):601-608). In some embodiments, the ISI is collectedin subjects ≥18 years or older. In some embodiments, the ISI in asubject after administration of an interleukin-1 receptor-Fc fusion isimproved to less than 14, or between 8-14, or less than 7. In someembodiments, administration of the interleukin-1 receptor-Fc fusionresults in the ISI of less than or equal to 7 in the subject beingtreated. In some embodiments, ISI score is less than or equal to 7 in atleast 50% of the subjects who receive interleukin-1 receptor-Fc fusionprotein. In some embodiments, ISI score is less than or equal to 7 in atleast 75% of the subjects who receive interleukin-1 receptor-Fc fusionprotein. In some embodiments, ISI score is less than or equal to 7 in atleast 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the subjects whoreceive interleukin-1 receptor-Fc fusion protein.

In some embodiments, the effectiveness of treatment with aninterleukin-1 receptor-Fc fusion protein is determined by a reduced riskof pericarditis recurrence compared to a no-treatment or placebocontrol. In some embodiments, administration of the interleukin-1receptor-Fc fusion results in reduced risk of pericarditis recurrence ofless than 50%, less than 40%, less than 30%, less than 20%, less than10%, less than 5%, less than 2%, or less than 1% or less than 0.5% orless than 0.25% or less than 0.1% based on statistical analysis ofpatients population being treated with an interleukin-1 receptor-Fcfusion protein according to the present invention.

In some embodiments, the effectiveness of treatment with aninterleukin-1 receptor-Fc fusion protein is determined by arecurrence-free period during or subsequent to the treatment. Arecurrence-free period of survival typically means that the subject doesnot experience an episode or occurrence of one or more symptoms ofpericarditis or a flare of inflammation during the period. Apericarditis recurrence or flare is usually indicated by any one or moreof the following: an increase in the CRP level of ≥1 mg/dl in peripheralblood; or an increase in pain, determined in an NRS scale of ≥4; oroccurrence of pericardial effusion (e.g., as determined by ECG or ECHO);a pericardial rub; or fever or any other symptomatic indication of thepericardial disease (e.g., as determined by PGIPS, PGA-PA, SF-36,EQ-5D-5L, or ISI). In some embodiments, a subject continues to receive atherapeutic dose of interleukin-1 receptor-Fc fusion protein at anadministrative interval and treatment period in accordance to theinvention during the recurrence-free period. In some embodiments, asubject may be gradually weaned of interleukin-1 receptor-Fc fusionprotein treatment during the recurrence-free period.

In some embodiments, the effectiveness of treatment with an interleukin1 receptor-Fc fusion protein is determined by the time period ofrecurrence-free survival (for examples, Days to flare). In someembodiments, the recurrence-free survival period is at least 30 days, 40days, 50 days, 60 days, 70 days, 80 days, or 90 days from the firstadministration of the interleukin-1 receptor-Fc fusion protein. In someembodiments, the recurrence-free survival period is at least 91 days, 92days, 93 days, 94 days, 95 days, 96 days, 97 days, 98 days, 99 days, 100days from the first administration of the interleukin-1 receptor-Fcfusion protein. In some embodiments, the recurrence-free survival periodis at least 105 days, or at least 110 days, or at least 115 days, or atleast 120 days, or at least 130 days, or at least 140 days, or at least150 days. In some embodiments, the recurrence-free survival period is atleast 200 days or more, while receiving interleukin 1 receptor-Fc fusionprotein at an administration interval (e.g., a weekly dose) andtreatment period according to the invention.

In some embodiments, the recurrence-free survival period is at least 30days, 40 days, 50 days, 60 days, 70 days, or at least 80 days from thewithdrawal of a pain medicine, or NSAID, while receiving weekly dose ofthe interleukin 1 receptor-Fc fusion protein. In some embodiments, therecurrence-free survival period from the withdrawal of NSAID is at least81 days, 82 days, 83 days, 84 days, 85 days, 86 days, 87 days, 88 days,89 days, 90 days, 91 days, 92 days, 93 days, 94 days, 95 days, 96 days,97 days, 98 days, 99 days, 100 days, 110 days, 120 days, 130 days, 140days, 150 days, 160 days, 170 days, 180 days, 190 days or 200 days ormore, while receiving interleukin 1 receptor-Fc fusion protein at anadministration interval (e.g., a weekly dose) and treatment periodaccording to the invention.

In some embodiments, the recurrence-free survival period is at least 50days from the withdrawal of a corticosteroid, while receiving weeklydose of interleukin 1 receptor-Fc fusion protein. In some embodimentsthe flare-free survival period from the withdrawal of NSAID is at least55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days,95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 160days, 170 days, 180 days, 190 days or 200 days or more, while receivinginterleukin 1 receptor-Fc fusion protein at an administration interval(e.g., a weekly dose) and treatment period according to the invention.

Adverse Effects

Adverse effects related to the treatment of pericarditis can includeinjection-site reaction, upper respiratory tract infection, headache,nausea, vomiting, diarrhea, sinusitis, arthralgia, flu-like symptoms,abdominal pain, pyrexia, herpes, transaminase elevation, ischemic opticneuropathy and nasopharyngitis.

In some embodiments, administration of an interleukin-1 receptor-Fcfusion protein results in no serious adverse events in the subject. Insome embodiments, administration of an interleukin-1 receptor-Fc fusionprotein does not result in one or more of injection-site reaction,worsening of rheumatoid arthritis, upper respiratory tract infection,headache, nausea, vomiting, diarrhea, sinusitis, ischemic opticneuropathy, arthralgia, flu-like symptoms, abdominal pain, pyrexia,herpes, transaminase elevation and nasopharyngitis.

In some embodiments, the various safety assessments includepharmacokinetic and pharmacodynamic monitoring, including but notlimited to: physical examination, measurement of vital signs, monitoringadverse event (AE), monitoring chest X-ray and screening for signs oftuberculosis.

Interleukin-1 (IL-1) Receptor-Fc Fusion Proteins

In some embodiments, inventive compositions and methods provided by thepresent invention are used to deliver an interleukin-1 receptor-Fcfusion protein to a subject in need. In certain embodiments of theinvention, the interleukin-1 receptor-Fc fusion proteins are recombinantfusion proteins that block IL-1 signaling by acting as a soluble decoyreceptor that binds IL-1α and IL-1β (i.e., an IL-1 trap) and preventstheir interaction with IL-1 cell surface receptors. In certainembodiments, the fusion protein comprises human cytokine receptorextracellular domains and an Fc portion of human immunoglobulin. In someembodiments, the Fc portion is from a human IgG1, IgG2, or IgG4. In someembodiments, the Fc portion comprises CH2 and CH3 domains derived from ahuman IgG1, IgG2 or IgG4. In one embodiment, the Fc portion comprises aCH2 domain derived from a human IgG4 and a CH3 domain derived from ahuman IgG1. In some embodiments, the Fc portion comprises at least aportion of the hinge region derived from a human IgG1. In someembodiments, the fusion protein comprises the extracellular domains ofIL-1R Type 1 and IL-1R accessory protein (IL-1RAcP). In someembodiments, two identical fusion proteins comprising the extracellulardomains of IL1R Type 1 and IL-1RAcP and an Fc portion of human IgG1 arecovalently linked by disulfide bonds in the Fc region to form ahomodimer. In one embodiment, the interleukin-1 receptor-Fc fusionprotein is rilonacept.

Interleukin-1 Receptor-Fc Fusion Protein Sequence (SEQ ID NO: 1)SERCDDWGLDTMRQIQVFEDEPARIKCPLFEHFLKFNYSTAHSAGLTLIWYWTRQDRDLEEPINFRLPENRISKEKDVLWFRPTLLNDTGNYTCMLRNTTYCSKVAFPLEVVQKDSCFNSPMKLPVHKLYIEYGIQRITCPNVDGYFPSSVKPTITWYMGCYKIQNFNNVIPEGMNLSFLIALISNNGNYTCVVTYPENGRTFHLTRTLTVKVVGSPKNAVPPVIHSPNDHVVYEKEPGEELLIPCTVYFSFLMDSRNEVWWTIDGKKPDDITIDVTINESISHSRTEDETRTQILSIKKVTSEDLKRSYVCHARSAKGEVAKAAKVKQKVPAPRYTVEKCKEREEKIILVSSANEIDVRPCPLNPNEHKGTITWYKDDSKTPVSTEQASRIHQHKEKLWFVPAKVEDSGHYYCVVRNSSYCLRIKISAKFVENEPNLCYNAQAIFKQKLPVAGDGGLVCPYMEFFKNENNELPKLQWYKDCKPLLLDNIHFSGVKDRLIVMNVAEKHRGNYTCHASYTYLGKQYPITRVIEFITLEENKPTRPVIVSPANETMEVDLGSQIQLICNVTGQLSDIAYWKWNGSVIDEDDPVLGEDYYSVENPANKRRSTLITVLNISEIESRFYKHPFTCFAKNTHGIDAAYIQLIYPVTNSGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKInterleukin-1 Receptor-Fc Fusion Protein Sequence with N-Terminus Signal Sequence (SEQ ID NO: 2)MVLLWCVVSLYFYGILQSDASERCDDWGLDTMRQIQVFEDEPARIKCPLFEHFLKFNYSTAHSAGLTLIWYWTRQDRDLEEPINFRLPENRISKEKDVLWFRPTLLNDTGNYTCMLRNTTYCSKVAFPLEVVQKDSCFNSPMKLPVHKLYIEYGIQRITCPNVDGYFPSSVKPTITWYMGCYKIQNFNNVIPEGMNLSFLIALISNNGNYTCVVTYPENGRTFHLTRTLTVKVVGSPKNAVPPVIHSPNDHVVYEKEPGEELLIPCTVYFSFLMDSRNEVWWTIDGKKPDDITIDVTINESISHSRTEDETRTQILSIKKVTSEDLKRSYVCHARSAKGEVAKAAKVKQKVPAPRYTVEKCKEREEKIILVSSANEIDVRPCPLNPNEHKGTITWYKDDSKTPVSTEQASRIHQHKEKLWFVPAKVEDSGHYYCVVRNSSYCLRIKISAKFVENEPNLCYNAQAIFKQKLPVAGDGGLVCPYMEFFKNENNELPKLQWYKDCKPLLLDNIHFSGVKDRLIVMNVAEKHRGNYTCHASYTYLGKQYPITRVIEFITLEENKPTRPVIVSPANETMEVDLGSQIQLICNVTGQLSDIAYWKWNGSVIDEDDPVLGEDYYSVENPANKRRSTLITVLNISETESRFYKHPFTCFAKNTHGIDAAYIQLIYPVTNSGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK  Extracellular Domain of IL-1RAcP Amino Acid Sequence(SEQ ID NO: 3) SERCDDWGLDTMRQIQVFEDEPARIKCPLFEHFLKFNYSTAHSAGLTLIWYWTRQDRDLEEPINFRLPENRISKEKDVLWFRPTLLNDTGNYTCMLRNTTYCSKVAFPLEVVQKDSCFNSPMKLPVHKLYIEYGIQRITCPNVDGYFPSSVKPTITWYMGCYKIQNFNNVIPEGMNLSFLIALISNNGNYTCVVTYPENGRTFHLTRTLTVKVVGSPKNAVPPVIHSPNDHVVYEKEPGEELLIPCTVYFSFLMDSRNEVWWTIDGKKPDDITIDVTINESISHSRTEDETRTQILSIKKVTSEDLKRSYVCHARSAKGEVAKAAKVKQKVPAPRYTVE Extracellular Domain of IL-1R1 Amino Acid Sequence (SEQ ID NO: 4)KCKEREEKIILVSSANEIDVRPCPLNPNEHKGTITWYKDDSKTPVSTEQASRIHQHKEKLWFVPAKVEDSGHYYCVVRNSSYCLRIKISAKFVENEPNLCYNAQAIFKQKLPVAGDGGLVCPYMEFFKNENNELPKLQWYKDCKPLLLDNIHFSGVKDRLIVMNVAEKHRGNYTCHASYTYLGKQYPITRVIEFITLEENKPTRPVIVSPANETMEVDLGSQIQLICNVTGQLSDIAYWKWNGSVIDEDDPVLGEDYYSVENPANKRRSTLITVLNISETESRFYKHPFTCFAKNTHGIDAAYIQLIYPVTN  Fc (IgG1) Amino Acid Sequence (SEQ ID NO: 5)DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 

In some embodiments of the invention, an interleukin-1 receptor-Fcfusion protein comprises an amino acid sequence of SEQ ID NO: 1. In someembodiments of the invention, an interleukin-1 receptor-Fc fusionprotein comprises an amino acid sequence of SEQ ID NO: 2. In someembodiments of the invention, an interleukin-1 receptor-Fc fusionprotein comprises an amino acid sequence at least 90% identical SEQ IDNO: 1. In some embodiments of the invention, an interleukin-1receptor-Fc fusion protein comprises an amino acid sequence with atleast 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% ormore identity to SEQ ID NO: 1.

In some embodiments of the invention, an interleukin-1 receptor-Fcfusion protein comprises an amino acid sequence with at least 75%, 80%,85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identityto SEQ ID NO: 3. In some embodiments of the invention, an interleukin-1receptor-Fc fusion protein comprises an amino acid sequence with atleast 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% ormore identity to SEQ ID NO: 4. In some embodiments of the invention, aninterleukin-1 receptor-Fc fusion protein comprises an amino acidsequence with at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99% or more identity to SEQ ID NO: 5.

The invention contemplates treatment of pericarditis using an agentcapable of reducing interleukin 1 receptor engagement, activity orexpression, thereby achieving the biological effect comparable to theinterleukin-1 receptor-Fc fusion protein treatment. In some aspects, thepericarditis is related to PCIS. In some aspects, the pericarditis isrelated to PPS. In some embodiments, the agent capable of reducinginterleukin receptor engagement is an interleukin-1 antagonist. In someembodiments, the invention provides a method of treating PCIS or PPSpericarditis by administering to the subject in need a therapeuticallyeffective amount of an interleukin-1 antagonist at a suitableadministration interval for a period as to improve, stabilize ordecrease at least one or more symptoms associated with the disease. Insome embodiments, the interleukin-1 antagonist is an interleukin-1binding protein. In some embodiments, the interleukin-1 antagonist is areceptor for interleukin-1 or a fragment thereof. In some embodiments,the interleukin-1 antagonist is an antibody or a fragment thereof. Insome embodiments, the interleukin-1 antagonist is an interleukin-1receptor fusion protein. In some embodiments the agent is aninterleukin-1 receptor antagonist (IL-1ra).

As is easily comprehensible by one of skill in the art, the agent can bean IL-1 receptor blocking antibody or fragment thereof, an IL-1antigen-binding protein, an IL-1 antibody or a fragment thereof, anantagonist of IL-1 receptor, an inhibitor of IL-1 receptor, an inhibitorof IL-1 receptor activation, an inhibitor of the IL-1 receptor mediatedsignaling, an inhibitor peptide capable of blocking IL-1 receptorsignaling, an inhibitor peptide capable of blocking or otherwisereducing IL-1 interaction with IL-1 receptor, an inhibitor RNA ornucleic acid which reduces the expression of an IL-1 receptor ligand oran IL-1 receptor. The present disclosure therefore encompasses obviousvariants of the invention that achieves the same purpose by using one ormore of conventional methods known to one of skill in the art to targetIL-1 receptor activation pathway for treating pericarditis.

EXAMPLES

While certain methods of the present invention have been described withspecificity in accordance with certain embodiments, the followingexamples serve only to illustrate the methods of the invention and arenot intended to limit the same.

Example 1: Treatment of Pericarditis with IL-1 Receptor-Fc FusionProtein

The study in this example was a Phase II clinical trial designed toevaluate the safety, tolerability, and PK of rilonacept, aninterleukin-1 receptor-Fc fusion protein, in subjects with pericarditis.The study also included exploratory investigations of the effect of theinterleukin-1 receptor-Fc fusion protein on clinical effect assessmentsin symptomatic patients.

Rilonacept is a recombinant fusion protein including the extracellulardomains of human IL-1 cytokine receptor and the Fc portion of humanimmunoglobulin G1 (IgG1) (SEQ ID NO:1). It acts as a soluble decoyreceptor binding IL 1α/IL 1β and prevents their interaction with the IL1 cell surface receptor.

Study drug (rilonacept or placebo) is supplied in a single use, 20 mlglass vial containing a sterile, white to off white, lyophilized powder.Each vial is to be reconstituted with 2.3 ml sterile Water for Injection(WFI). A volume up to 2 ml can be withdrawn, which is designated todeliver up to 160 mg of rilonacept or up to 2 ml of placebo for SCinjection only. The resulting solution is clear, colorless to paleyellow, and essentially free of particulates.

Each rilonacept vial contains 220 mg of rilonacept lyophilized powder.After reconstitution with 2.3 ml WFI, the rilonacept vial contains 80mg/ml rilonacept, 40 mM histidine, 50 mM arginine, 3.0% (w/v)polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine ata pH of 6.5. No preservatives are present.

Study Design

Participating subjects receive a total of 6 weekly doses of theinterleukin-1 receptor-Fc fusion protein. Dosing is initiated with aloading dose of 320 mg administered subcutaneously as two 160 mg doses,followed by 160 mg maintenance doses administered subcutaneously once aweek. Pericarditis improvement data and safety information arecollected. If subjects are deemed to be responsive to treatment,participation in an optional 18 week extension period may be offered.For the duration of the Treatment Period, concomitant NSAIDs and/orcolchicine and/or corticosteroids, if present, should be continued atpre-study dose levels until after the 6 dose Treatment Period hasconcluded; however, should if it is determined that a reduction/taperingof the NSAID, colchicine, and/or corticosteroid dose is medicallyindicated, the NSAID, colchicine, and/or corticosteroid dose can bedown-titrated.

Opioid analgesics, non-narcotic analgesics (e.g., tramadol), andacetaminophen are allowed as rescue medication for ancillary paincontrol on an as-needed basis throughout the Treatment Period. Althoughit is recommended that NSAID dose levels (if present) should remainconstant during the active Treatment Period, the concomitant NSAID dosemay be temporarily increased (or an NSAID initiated) for ancillary paincontrol if deemed necessary. At the discretion of the Investigator,“Treatment Responders” (defined by the investigator as a clinicallysignificant reduction in pericardial pain using the 11-point NRS, normalor near-normal CRP levels, and/or absent or decreasing echocardiographiceffusion at the End-of-Trial Visit), will be offered participation in anoptional 18-week Extension Period (EP), in which weekly administrationof interleukin-1 receptor-Fc fusion protein can be continued at the samedose as in the Treatment Period for a total duration of treatment of upto 24 weeks. During the EP, the Investigator may choose to weanconcomitant NSAIDs, colchicine, and/or corticosteroids according tostandard of care paradigms.

Study Treatments

The interleukin-1 receptor-Fc fusion protein was prepared as alyophilized formulation. For subcutaneous (SC) administration, theinterleukin-1 receptor-Fc fusion protein was manufactured in a dosageform containing 160 mg per vial. The lyophilized powder wasreconstituted with 2.3 mL of sterile Water for Injection (WFI) and drugwas delivered in 2 mL at a concentration of 80 mg/mL. Dosing initiatedwith a loading dose of 320 mg administered subcutaneously as two 160 mgdoses, followed by 160 mg maintenance doses were administeredsubcutaneously once a week. After an initial group of subjects weretreated, depending on the safety profile observed as well as themagnitude and speed of treatment response (e.g., if an informativenumber of subjects achieve treatment responded early in the TreatmentPeriod), the protocols allows for the dose administered to a subsequentgroup of subjects to be decreased to loading dose of 160 mg (2×80 mg)administered SC, followed by 80 mg maintenance dose administered SC oncea week for 5 additional weeks, in order to determine efficacy at a lowerdose.

Subject Inclusion Criteria

Subjects who have had an index episode of pericarditis which, based onthe available data, met the criteria for an acute pericarditis event,using the 2015 ESC Guidelines for the Diagnosis and Management ofPericardial Diseases (Adler et al, European Heart Journal, Volume 36,issue 42, 7 Nov. 2015, Pages 2921-2964) as a frame of reference—i.e.,met at least 2 of the 4 following criteria: pericarditic chest pain,pericardial rubs, new widespread ST-segment elevation or PR-segmentdepression on ECG, and pericardial effusion (new or worsening).Additional supporting findings included elevations of markers ofinflammation (i.e., CRP, erythrocyte sedimentation rate, and white bloodcell count) or evidence of pericardial inflammation by an imagingtechnique (e.g., MRI).

Subjects also had to have had at least one prior recurrent episode ofpericarditis, and subjects had to have an ongoing symptomatic episode ofpericarditis at the time of study enrollment, both based upon theavailable diagnostic information. Also, if a subject used NSAIDs, and/orcolchicine and/or corticosteroids (in any combination), they must havereceived at stable dose levels for at least 7 days prior to initialdosing (although stable doses for at least 3 days were acceptable if ashorter period of stability was not anticipated to alter the baselineCRP values) with the interleukin-1 receptor-Fc fusion protein and thesubject was expected to continue these concomitant medications at thesedose levels for the duration of the active Treatment Period.

The phase 2 open-label pilot study is a 24-week study in up to 40subjects in total, age 6 to 75 years old, including the followingcategories of subjects with recurrent pericarditis, referred as thefollowing Groups:

Group 1 enrolling symptomatic subjects with recurrent idiopathicpericarditis (RIP) with an elevated marker of systemic inflammation(C-reactive protein [CRP]≥1 mg/dL);

Group 2 enrolling symptomatic subjects with RIP with CRP<1 mg/dL which,in the opinion of the investigator could be attributed to concomitantmedications (e.g., corticosteroids) and with pericardial inflammationpresent on cardiac magnetic resonance imaging (MM), confirmed by theimaging core lab;

Group 3 enrolling subjects with corticosteroid-dependent RIP notexperiencing symptoms which would meet the diagnostic criteria for aflare of pericarditis;

Group 4 enrolling symptomatic subjects with recurrent postpericardiotomy syndrome (PPS) with an elevated marker of systemicinflammation (CRP≥1 mg/dL); and

Group 5 enrolling subjects with corticosteroid-dependent recurrent PPSnot experiencing symptoms which would meet the diagnostic criteria for aflare of pericarditis.

Study Assessments

Blood samples were collected and C-reactive protein (CRP) levels weredetermined both before study inclusion of a subject and during thestudy. Some subjects presented with elevated CRP values ≥1 mg/dL at thetime of study enrollment. CRP changes and the time course to decreaseand resolution of CRP to normal values <0.5 mg/dL were assessed.

The following clinical response assessments were also conducted duringthe study.

Echocardiograms (ECHOS) including assessment of pericardial effusionwere performed at screening (SCV1); at Study Site/Clinic visits duringthe Treatment Period (Interval Evaluation Visit, which, if applicable,occurred during approximately weeks 3-4 of the Treatment Period andVisit 7/End-of-Trial); at the Interval Evaluation Visit during the EP[if applicable]; and at the Final Study Visit/Visit 8 (SCV8).Pericardial effusion was characterized by accumulation of excess fluidin the pericardial space surrounding the heart and was one of the commonfeatures of pericarditis. Echocardiography is a sensitive tool and themost widely used imaging technique for the detection of pericardialeffusion and/or thickening. For the purposes of the analysis oftreatment response in all subjects at the end of the study, all ECHOimages were assessed by a central reader.

Twelve-lead electrocardiograms (ECGs) were performed at screening (SCV1and optional SCV2), at Study Site/Clinic visits during the TreatmentPeriod (Interval Evaluation Visit [if applicable] and Visit7/End-of-Trial), at the Interval Evaluation Visit during the ExtensionPeriod (EP) [if applicable], and at the Final Study Visit/Visit 8.Pericarditis commonly involves changes in the electrophysiologicactivity of the heart, resulting in typical ECG findings, namelywidespread ST-elevation or PR depression. Changes in ECG findings helpdetermine the pericarditis status of a subject. For the purposes of theanalysis of treatment response in all subjects at the end of the study,all ECG tracings were assessed by a central reader.

Common pericarditis signs include fever and pericardial rub. Thesepericarditis signs were assessed via documentation of vital signs andphysical examinations. Physical examinations and vital signs assessmentsfor pericarditis signs were performed at screening (SCV1 and optionalSCV2), at Study Site/Clinic visits during the Treatment Period (IntervalEvaluation Visit [if applicable] and Visit 7/End-of-Trial), at theInterval Evaluation Visit during the EP [if applicable], and the FinalStudy Visit/Visit 8. If applicable, assessment of pericarditis signswere also performed at unscheduled visits.

Common pericarditis symptoms include chest discomfort (pericarditispain). A validated 11-point Numerical Rating Scale (NRS) was used tomeasure the subject's level of pericarditis (chest) pain intensity(Mannion et al, Nature Clinical Practice Rheumatology 2007; 3 (11):610-18). The assessment was performed at all study visits on-site duringStudy Site/Clinic visits and as part of telephone calls/virtual visitsduring outpatient visits/treatment weeks (weekly during the TreatmentPeriod and monthly during the EP).

Cardiac MRI was an optional assessment and could be performed at studyentry (SCV1) and at the final study visit (Visit 8) to assess anychanges in pericardial inflammation. For the purposes of the analysis oftreatment response in all subjects at the end of the study, all cardiacMill images was to be assessed by a central reader.

A validated Quality of Life Questionnaires was used to assess changes inthe subject's overall well-being (Hays et al, Qual Life Res (2009)18:873-880). The patient's global assessment was performed at screening(SCV1), at Visit 1 (Day 0), at the end of the Treatment Period (Visit7/End-of-Trial), at the Interval Evaluation Visit during the EP, and atthe Final Visit (Visit 8).

An adverse event (AE) is any untoward medical occurrence in a subject orclinical investigation subject administered a pharmaceutical product. AnAE does not necessarily have a causal relationship with this treatment.An AE can therefore be any unfavorable and/or unintended sign (includingan abnormal laboratory finding), symptom or disease temporallyassociated with the use of a medicinal (investigational) product,whether or not related to the medicinal (investigational) product.

AEs also include: any worsening (i.e., any clinically significant changein frequency and/or intensity) of a pre-existing condition that istemporally associated with the use of the interleukin-1 receptor-Fcfusion protein; abnormal laboratory findings considered by the reportinginvestigator to be clinically significant; and any untoward medicaloccurrence.

In this study, individual elements of pericarditis symptomatology(including pain) are captured as an efficacy parameter. Pericarditispain is not required to be reported as an AE. However, if the subjectexperiences new symptoms that had not been previously reported in theconstellation of symptoms recorded at baseline, these new symptomsshould be reported as an adverse event.

Primary efficacy endpoints include inter- and intra-subject variabilityestimates for CRP and the 11-point NRS instrument in symptomaticsubjects with RIP both at baseline and while on the interleukin-1receptor-Fc fusion protein treatment. Exploratory endpoints include thefollowing: time course of improvement of measures of pericarditissymptomatology, including pericarditis pain, CRP, and/or resolution ofechocardiographic and ECG abnormalities; differential response todifferent interleukin-1 receptor-Fc fusion protein doses (e.g., 160 mgor 80 mg maintenance doses); time to CRP normalization (≤0.5 mg/dL);change over time in CRP levels; number (percentage) of subjects withnormalization of CRP; change over time in subjects' assessments ofpericarditis pain; explore Patient-Reported Outcome (PRO), biochemical(CRP), and imaging correlates of clinical improvement of pericarditissymptomatology in order to develop a suitable composite primary endpointfor subsequent clinical trials in RIP; number (percentage) of subjectswith pericarditis improvement (based on investigator assessment); changeover time in subjects' global assessments of overall well-being (usingthe QoL instrument); change in pericardial inflammation as assessed bycardiac MRI; number of subjects weaned off NSAIDs, colchicine, and/orcorticosteroids at end of the EP; time to pericardial flare, the numberof patients experiencing recurrence of pericarditis and the number ofrecurrences of pericarditis.

Example 2: Reduction in CRP Levels and Pain with Interleukin-1Receptor-Fc Fusion Protein

This example demonstrates that the Phase II clinical trial described inExample 1 resulted in clinically meaningful efficacy, particularlyclinically significant reduction in CRP levels and pain.

Specifically, fourteen patients (subjects) having pericarditis weretreated with a 320 mg loading dose of subcutaneously injectedinterleukin-1 receptor-Fc fusion protein (rilonacept) at day 0, followedby 160 mg maintenance dose of subcutaneously injected rilonacept once aweek. CRP levels and pain scores (using an 11-point Numerical RatingScale (NRS)) for these patients are shown in FIGS. 1A-3C. Nine patientswere enrolled in Group 1 (symptomatic idiopathic recurrent pericarditissubjects with elevated CRP), and six patients showed a reduction in CRPand NRS (pain) values even after a single dose of the treatment as shownin FIGS. 1A-C, E, and H-I. In the case of Subject D, the CRP level wasnot tested one week after the initial dose of rilonacept; however, atthe second week of treatment, the CRP value showed a marked reductioncompared to baseline (FIG. 1D). Subject F and G showed reduction in CRPlevels as shown in FIGS. 1F and 1G. Each patient was being treated withprior medications for pain and/or inflammation at the indicated dosesshown in FIGS. 1A-I. All Group 1 patients showed a trend towards apersistent reduction in pain and CRP values during subsequent dosingperiods compared to baseline as shown in FIGS. 1A-I. As shown in FIG.1C, after 6 weeks of rilonacept therapy, Subject C in Group 1 stoppedtaking ibuprofen and after approximately 8 weeks (55 days) of beingtreated with rilonacept this subject began a six week taper ofprednisone. The subject's dose was reduced by 2.5 mg every other week.The subject has remained asymptomatic in the absence of ibuprofen andduring the steroid weaning period, while continuing rilonacept therapyduring the extension period. As shown in FIG. 1C, the subject proceededthrough the next 77 days with neither ibuprofen nor prednisone,exhibiting no flare or recurrence, CRP level <0.5 mg/dl, and no pain.

Two patients were enrolled in Group 2 (symptomatic RIP subjects withCRP<1 mg/dL and with pericardial inflammation present on cardiac Mill)and showed a reduction in CRP and pain even after a single dose of thetreatment, and continued to show a trend towards a reduction in pain andCRP values during the subsequent dosing period compared to baseline asshown in FIGS. 2A and 2B. These patients were being treated with priormedications for pain and inflammation at the indicated doses shown inthe figures. Three patients were enrolled in Group 3 (subjects withcorticosteroid-dependent RIP not experiencing symptoms which would meetthe diagnostic criteria for a flare of pericarditis), but were judged bythe investigator as corticosteroid-dependent, i.e., based upon priorhistory and experience that the signs and symptoms of pericarditis wouldreturn if the corticosteroids were withdrawn. These patients were beingtreated with prior medications for pain and inflammation at theindicated doses shown in FIGS. 3A, 3B and 3C. After receiving rilonacept(320 mg) at day 0 and prior to withdrawal of concurrent therapies, thepatient remained asymptomatic as observed on day 7. During the extensionperiod of the study, the protocol allows the subjects enrolled in Group3 to be weaned from concomitant pericarditis medications, includingsteroids, while remaining on rilonacept at the discretion of the medicalpractitioner. For example, FIG. 3B shows that the patient exhibitedreduced CRP level and NRS score even at the tapering of prednisone doseto complete weaning at 91 days after the first dose of rilonacept.Subject B continued to show the reduced CRP level and NRS score over thenext 28 days of prednisone-free regime, as shown in FIG. 3B. Subject Aof Group 3 opted out of the extension study at completion of the basetreatment period. Additional outcome measures, such as presence ofeffusion, QoL and ECG changes, acquired from subjects in Groups 1-3 arereported in FIG. 5. Adverse events reports for these subjects are shownin Table 2.

Twelve subjects treated with rilonacept have reported some mild adverseevents (AEs) (Table 2). None were serious, and none led todiscontinuation of study drug. The most commonly reported AEs wereinjection-site reactions, and all were mild and transient in nature.These results demonstrate that interleukin-1 receptor-Fc fusion proteinis safe and efficacious for human treatment.

TABLE 2 Subject Reported Term Relationship Action Taken Outcome of IDfor Adverse Event Severity Serious to Study Drug on Study Drug AdverseEvent Group 1 ISR Redness Mild No Possibly None Recovered/ SubjectRelated Resolved B Group 1 ISR Warmness Mild No Possibly None Recovered/Subject Related Resolved B Group 1 Headache Mild No Not None Recovered/Subject Related Resolved E Group 1 Vertigo Mild No Possibly NoneRecovered/ Subject Related Resolved E Group 1 Toothache Mild No Not NoneRecovered/ Subject Related Resolved E Group 1 RT Dry Eye Mild No NotNone Not Subject Related Recovered/ F Not Resolved Group 1 Applicationsite Mild No Not None Recovered/ Subject redness Related Resolved DGroup 1 Application site Mild No Not None Recovered/ Subject bruiseRelated Resolved D Group 1 Heartburn Mild No Unlikely None Recovered/Subject Related Resolved A Group 1 Common cold Mild No Unlikely NoneRecovered/ Subject Related Resolved A Group 1 Injection site Mild NoRelated None Recovered/ Subject reaction Resolved A Group 1 Worsening ofMild No Possibly None Recovered/ Subject elevated LFTs** RelatedResolved A Group 1 Elevated HDL Mild No Related None Not SubjectRecovered/ A Not Resolved Group 1 Elevated CK Mild No Unlikely NoneRecovered/ Subject Related Resolved A Group 1 Intermittent Mild NoPossibly None Not Subject chest discomfort Related Recovered/ A ResolvedGroup 3 Soreness at Mild No Related None Recovered/ Subject injectionsite Resolved A Group 3 Pain with Mild No Not None Recovered/ Subjectinspiration Related Resolved A Group 3 Dry cough Mild No Unlikely NoneRecovered/ Subject Related Resolved A Group 3 Hand muscle Mild NoUnlikely None Recovered/ Subject pain Related Resolved A Group 3Worsening Mild No Possibly None Not Subject shortness of RelatedRecovered/ A breath when Not Resolved lying flat Group 3 Worsening ofMild No Not None Not Subject elevated liver Related Recovered/ Aenzymes* Not Resolved Group 3 Shortness of Mild No Possibly None NotSubject breath Related Recovered/ B Not Resolved Group 3 Fatigue Mild NoUnlikely None Not Subject Related Recovered/ B Not Resolved Group 3Worsening Mild No Possibly None Recovered/ Subject pericarditis RelatedResolved B symptoms Group 3 Injection site Mild No Related NoneRecovered/ Subject reaction Resolved B Group 3 Elevated Mild No RelatedNone Not Subject cholesterol Recovered/ B Not Resolved Group 3 BilateralMild No Unlikely None Not Subject shoulder pain Related Recovered/ B NotResolved Group 3 Injection site Mild No Related None Recovered/ Subjectreaction Resolved C Group 1 Pain at injection Mild No Related NoneRecovered/ Subject site Resolved C Group 1 Intermittent Mild No PossiblyNone Recovered/ Subject muscle Related Resolved C twitching - bilateralthighs Group 1 Hemorrhoids Mild No Not None Recovered/ Subject RelatedResolved C Group 1 Nausea Mild No Not None Recovered/ Subject RelatedResolved C Group 1 Cold Mild No Possibly None Recovered/ Subject RelatedResolved C Group 2 Redness at Mild No Related None Recovered/ Subjectinjection site Resolved A Group 1 Atypical Chest Moderate Yes UnlikelyNone Recovered/ Subject Pain Related Resolved G Group 1 Bruising at MildNo Related None Recovered/ Subject injection site Resolved G Group 1Right lower Mild No Unlikely None Recovered/ Subject extremity RelatedResolved G cellulitis Group 1 Chest pain Mild No Not None Recovered/Subject Related Resolved G Group 1 Diarrhea Mild No Unlikely NoneRecovered/ Subject Related Resolved H

Example 3. Long Term Efficacy of Interleukin-1 Receptor-Fc FusionProtein in Subjects with Recurrent Pericarditis

A Phase III, double blind, placebo controlled, randomized withdrawalstudy with open label extension, is designed to assess the efficacy andsafety of rilonacept treatment in subjects with recurrent pericarditis.The primary endpoint is time to pericarditis recurrence, defined as thetime from randomization to the date of the first pericarditis recurrencefor each subject. Only CEC-confirmed pericarditis recurrence will beconsidered as an event for the primary analysis. Primary analysis ofthis study is at the last (22^(nd)) CEC-confirmed pericarditisrecurrence and all subjects in the RW period have been treated for 24weeks. Subjects who have not had an adjudicated pericarditis recurrencewill be censored on the day of the last available assessment before datacutoff.

All suspected pericarditis recurrence events are formally adjudicated bythe Clinical Endpoint Committee (CEC), and only events that areconfirmed by the CEC as pericarditis recurrences are used in the PrimaryEndpoint analysis. A multitude of other endpoints are analyzed atvarious stages of the study as described in the following sections. Theoverview of the study is depicted in FIG. 4.

Subjects eligible for the study are subjects with recurrent pericarditiswho do not have pericarditis secondary to prohibited conditions. Thestudy population includes both adult subjects ≥18 years old andpediatric subjects ≥12 and <18 years old with a history of at least 2prior pericarditis episodes (including the first episode and 1recurrence). Enrollment of pediatric subjects are limited to up to 20%of the study population. To be eligible for the study, subjects mustpresent at screening with at least a third pericarditis episode, definedas at least 1 day with pericarditis pain measurement ≥4 on the 11-pointNumerical Rating Scale (NRS) and C-reactive protein (CRP) level ≥1 mg/dLwithin 7 days prior to first study drug administration. Pericarditispain ≥4 and CRP≥1 mg/dL are not required to be present on the same day.

Subjects included in the study may be receiving concomitant NSAIDsand/or colchicine and/or oral CS treatment in any combination, providedthat the dosages of these medications have been stable (or notincreased) for at least 3 days prior to first administration of studydrug, and that changes in medications made within this time period (forinstance, 1-time use of NSAIDs) are not anticipated by the investigatorto significantly alter assessments of baseline disease activity.

The study has 5 periods:

(1) Screening period, during which assessment of diseasecharacteristics, baseline therapy, and the pre-treatment workup iscompleted (up to 4 weeks)

(2) Single-blind Run-In (RI) period (12 weeks), during which blindedrilonacept (IL-1 receptor-Fc fusion protein, IL1RFcFP) is administeredSC once weekly in all subjects. The RI period includes the following:

-   -   1-week Stabilization period, during which blinded rilonacept is        administered in addition to standard of care (SOC) pericarditis        therapy and the ongoing pericarditis episode is treated.    -   9-week Weaning period, during which subjects are weaned off        background SOC pericarditis therapy, as applicable, while        treatment with blinded rilonacept continues. The dosages of        corticosteroids (CS), NSAIDs, and colchicine are tapered        according to the weaning protocol in the Pharmacy Manual (for        the purpose of the protocol, aspirin is considered an NSAID). In        general, CS doses are tapered off starting at RI Week 1 and are        withdrawn by RI Week 10 (over a total of 9 weeks). NSAID and        colchicine doses are tapered off starting at RI Week 4 and are        withdrawn by RI Week 10 (over a total of 6 weeks).    -   2-week Monotherapy period during which subjects who have        successfully weaned off background SOC pericarditis therapy        continue to receive blinded rilonacept.

In the single-blind RI period (subjects are blinded regarding the timeof transition from the single-blind to the double-blind period), adultsubjects ≥18 years old will receive rilonacept as an initial loadingdose of 320 mg (2 SC injections of 160 mg each) at the RI baseline visit(2×2 ml), followed by a 160 mg (2 ml) SC dose once weekly throughout theRI period. Pediatric subjects (≥12 and <18 years old) receive an initialloading dose of rilonacept 4.4 mg/kg (2 SC injections of 2.2 mg/kg each)at the RI baseline visit (maximum 2×2 ml), and then 2.2 mg/kg (maximum 2ml) SC once weekly throughout RI period. Subjects who stopped backgroundpericarditis medications and who achieve Clinical Response at RI Week12, defined as the weekly average of daily pericarditis pain score ≤2.0on the 11-point NRS within the 7 days prior to and including the day ofrandomization on RI Week 12 and a CRP level ≤0.5 mg/dL at RI Week 12/RWbaseline visit, proceed into the double-blind placebo-controlledRandomized-Withdrawal (RW) period. Subjects who do not achieve ClinicalResponse at RI Week 12 on rilonacept monotherapy are discontinued fromstudy drug, transitioned to SOC pericarditis therapy at theinvestigator's discretion, and followed through the end of the RWperiod.

The following secondary endpoints are assessed in this period:

-   -   Proportion of subjects who achieved Clinical Response. Clinical        Response is defined as a weekly average of daily pericarditis        pain of ≤2.0 on the 11-point NRS during the week preceding        randomization AND CRP level ≤0.5 mg/dL at RI Week 12/RW baseline        visit.    -   Time to CRP normalization (≤0.5 mg/dL)    -   Number (percentage) of subjects with normalization of CRP at RI        Week 12    -   Change from baseline in pericarditis pain at RI Week 12    -   Change from baseline in CRP level at RI Week 12    -   Resolution of ECHO and ECG abnormalities (yes/no) at RI Week 12    -   Percentage of days with no or minimal pain    -   Number (percentage) of subjects with absent or minimal        pericarditis symptoms based on PGIPS    -   Number (percentage) of subjects with absent or minimal        pericarditis activity based on the PGA-PA    -   Change over time in the SF-36 Physical Component Score    -   Change over time in the SF-36 Mental Component Score    -   Change in the EQ-5D-5L    -   Change over time in the subject's sleep quality assessed with        the ISI    -   Change over time in ISI categories    -   Number (percentage) of subjects who were off background        pericarditis medication at RI Week 12.

(3) Double-blind placebo-controlled RW period (pericarditis recurrenceevent-driven duration, with a minimum of 24 weeks).

The primary efficacy endpoint, that is the time of pericarditisrecurrence for each subject is determined at this stage. OnlyCEC-confirmed pericarditis recurrence is considered as an event for theprimary analysis.

Major secondary efficacy endpoints for the RW period include:

-   -   Proportion of subjects who maintained Clinical Response at Week        24 of the RW period    -   Percentage of days with no or minimal pain (pain ≤1 on the        11-point NRS) in the first 24 weeks of the RW period    -   Proportion of subjects with absent or minimal pericarditis        symptoms (based on the 7-point rating scale of PGIPS) at Week 24        of the RW period.

Other secondary endpoints for the RW period include:

-   -   Proportion of subjects without pericarditis recurrence in the        first 24 weeks of the RW period    -   Time to NRS≥4    -   Time to CRP level≥1 mg/dL    -   Time to pericardial rub    -   Time to widespread ST-segment elevation or PR-segment depression        on ECG    -   Time to new or worsening pericardial effusion on ECHO    -   Change over time in CRP levels    -   Change over time in subject's assessments of pericarditis pain        (weekly average)    -   Number (percentage) of subjects with absent or minimal        pericarditis activity based on the PGA-PA    -   Change over time in SF-36 Physical Component Score    -   Change over time in SF-36 Mental Component Score    -   Change in EQ-5D-5L    -   Change over time in subject's sleep quality assessed with the        ISI    -   Change over time in ISI categories    -   Number (percentage) of subjects who receive ORT therapy for        pericarditis recurrence (analgesics, NSAIDs, and/or colchicine)        in the RW period

During this stage, subjects who were able to stop backgroundpericarditis medication and who achieve Clinical Response at RI Week 12are randomized in a double-blind manner at a 1:1 ratio to the following:

-   -   Rilonacept 160 mg (2.2 mg/kg in pediatric subjects) SC        injections once weekly    -   Matching placebo SC injections once weekly

Subjects report pericarditis associated pain daily based on 11-pointpericarditis pain NRS scoring. A sensitivity analysis is done based onthe investigator's assessment of the event.

All statistical tests for the treatment comparison of efficacy endpointsin the RW period are based on the Intent-To-Treat (ITT) analysis setwith 1-sided α=0.025.

Pericarditis Recurrence in the RW Period

Pericarditis recurrence is defined as the recurrence of typicalpericarditis pain associated with supportive objective evidence ofpericarditis. Upon pericarditis recurrence, subjects who report at least1 day with pericarditis pain measurement ≥4 on the 11-point NRS and have1 CRP value ≥1 mg/dL (either on the same day or separated by no morethan 7 days) receive bailout rilonacept (2 open-label injections of 160mg rilonacept [or 4.4 mg/kg for pediatric subjects] followed byonce-weekly open-label rilonacept SC injections of 160 mg [or 2.2 mg/kgfor pediatric subjects]), irrespective of randomized treatmentassignment and as soon as at least 5 days have passed since the laststudy drug injection. Sequential Oral Rescue Therapy (ORT), i.e.,analgesics first, then NSAIDs, and then colchicine, can be added ifneeded at the discretion of the investigator, as outlined in theprotocol and Pharmacy Manual.

Subjects with pericarditis recurrence who do not meet the protocolcriteria for bailout rilonacept continue with the blinded study druguntil the protocol criteria for bailout rilonacept are met or throughthe end of the RW period. For those subjects, sequential ORT can beadded to blinded study drug at the discretion of the investigator, asoutlined in the protocol and Pharmacy Manual.

All suspected pericarditis recurrence events in the RW period areformally adjudicated by the Clinical Endpoint Committee (CEC), and onlyevents that are confirmed by the CEC as pericarditis recurrences areused in the Primary Endpoint analysis.

A subject experiencing a suspected pericarditis recurrence is requiredto contact the study investigator immediately for evaluation. Requiredassessments include:

-   -   Evaluation of pericarditis pain on 11-point NRS.    -   Evaluation of concomitant medications as well as pericarditis        concomitant medications.    -   Obtain laboratory samples for CRP (local and central) (the POC        device provided by Kiniksa Pharmaceuticals is the preferred        method for local laboratory CRP assessment).    -   Acquisition of a 12-lead ECG.    -   Acquisition of a cardiac ECHO per core laboratory imaging        parameters; this ECHO can be read locally for the purpose of        pericarditis recurrence assessment and then requires submission        to the ECHO core laboratory for central review.    -   Performing an abbreviated physical examination, height and body        weight.    -   Having subjects ≥18 years complete the SF-36, EQ-5D-5L, ISI    -   Having subjects complete the PGIPS score.    -   The investigator completes the PGA-PA.    -   Obtaining central laboratory samples for PK, ADAs, and        biomarkers.    -   Other procedures deemed necessary per the investigator or        delegated site personnel.

Upon the complete evaluation, if the investigator deems the subject tobe having a pericarditis recurrence event, he/she should contact the PPDmedical monitor to confirm that all assessments have been performed andcollected.

(4) Long Term Extension Treatment Period (LTE-TP) (24 weeks), duringwhich all subjects completing the RW period (including subjectstransitioned to open-label rilonacept upon pericarditis recurrence) havean option to receive up to 24 weeks of open-label rilonacept 160 mg (or2.2 mg/kg for pediatric subjects) SC injections once weekly based ontheir clinical status and at the discretion of the investigator, aftersigning LTE informed consent. Any subject who, in the opinion ofinvestigator, should not continue open-label rilonacept are offeredparticipation in the LTE off study drug and after signing LTE informedconsent.

The endpoints assessed in this phase are listed below. Each endpoint issummarized through Week 24, by subjects who do and do not have anadjudicated pericarditis recurrence in the RW period, respectively, andoverall:

-   -   Number (percentage) of subjects with pericarditis recurrences    -   Proportion of subjects with Clinical Response    -   Change over time in CRP levels    -   Change over time in the subject's assessments of pericarditis        pain    -   Percentage of days with no or minimal pain    -   PGIPS    -   PGA-PA    -   Change over time in the SF-36 Physical Component Score    -   Change over time in the SF-36 Mental Component Score    -   Change in the EQ-5D-5L    -   Change over time in the subject's sleep quality assessed with        the ISI    -   Change over time in ISI categories    -   Number (percentage) of subjects requiring addition of SOC        pericarditis therapy.

(5) Long Term Extension Follow-up Period (LTE-FUP) (24 weeks), duringwhich all subjects in the LTE-TP are followed in the LTE-FUP for safetyand potential pericarditis recurrences.

Efficacy and Safety Assessments

Efficacy assessments include the following: daily pericarditis pain onthe 11 point NRS in the subject's electronic diary, CRP level,electrocardiogram (ECG), echocardiography (ECHO), patient GlobalImpression of Pericarditis Severity (PGIPS), physician Global Assessmentof Pericarditis Activity (PGA-PA), 36 Item Short Form Health Survey (SF36), 5-Level EuroQoL-5D (EQ 5D 5L), insomnia Severity Index (ISI),cardiac magnetic resonance imaging (in a substudy in approximately 10subjects).

Pharmacokinetic or pharmacodynamic assessments include: PK analysis,anti-rilonacept antibodies, biomarkers, and/or peripheral bloodmononuclear cell isolation (for subjects who sign the separate informedconsent for pharmacogenomics assessments)

Safety assessments during the study will include: physical examination,vital signs measurements, adverse event (AE) monitoring, chest x ray,tuberculosis screening.

In order to control the overall 1 sided type I error rate at the 0.025level, a gatekeeping procedure in combination with Hochberg's procedurewill be applied to testing the primary and major efficacy secondaryendpoints.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. The scope of the presentinvention is not intended to be limited to the above Description, butrather is as set forth in the following claims:

We claim:
 1. A method of treating recurrent pericarditis comprisingadministering subcutaneously to a patient in need of treatment, aninterleukin-1 receptor-Fc fusion protein at 160 mg, wherein theinterleukin-1 receptor-Fc fusion protein comprises an extracellulardomain of IL-1R1, and an extracellular domain of IL-1R accessory protein(IL-1RAcP), wherein the extracellular domain of IL-1R1 comprises anamino acid sequence with at least 99% identity to SEQ ID NO: 4; andwherein the extracellular domain of IL-1RAcP comprises an amino acidsequence with at least 99% identity to SEQ ID NO:
 3. 2. The method ofclaim 1, wherein the extracellular domain of IL-1R1 comprises an aminoacid sequence set forth in SEQ ID NO:
 4. 3. The method of claim 1,wherein the extracellular domain of IL-1RAcP comprises an amino acidsequence set forth in SEQ ID NO:
 3. 4. The method of claim 1, whereinthe interleukin-1 receptor-Fc fusion protein comprises an Fc portion ofIgG1.
 5. The method of claim 1, wherein the interleukin-1 receptor-Fcfusion protein administered once every week.
 6. The method of claim 5,wherein the interleukin-1 receptor-Fe fusion protein is administered forone or more weeks.
 7. The method of claim 1, wherein the interleukin-1receptor-Fe fusion protein is a homodimer.
 8. The method of claim 1,wherein the patient in need of treatment has a recurrence ofpericarditis with pericarditis pain measurement ≥4 Numerical RatingScale (NRS) and C-reactive protein (CRP) level ≥1 mg/dL.
 9. The methodof claim 1, wherein the administration of the interleukin-1 receptor-Fefusion protein results in a treatment response defined by pericardialpain NRS ≤2 and CRP ≤0.5 mg/dL.
 10. The method of claim 9, wherein theNRS score is reduced to 2 or less within 7 days from the firstadministration of the interleukin-1 receptor-Fe fusion protein.
 11. Themethod of claim 9, wherein CRP level is reduced to <0.5 mg/dL within 7days from the first administration of the interleukin-1 receptor-Fefusion protein.
 12. The method of claim 1, wherein the administration ofthe interleukin-1 receptor-Fc fusion protein results in a withdrawal ofconcurrent therapy or standard of care treatment in the patient.
 13. Themethod of claim 12, wherein the concurrent therapy or standard of caretreatment is NSAIDs, steroid, colchicine, corticosteroid, orcombinations thereof.
 14. The method of claim 13, wherein theadministration of the interleukin-1 receptor-Fc fusion protein resultsin withdrawal of corticosteroid treatment in the patient.
 15. The methodof claim 14, wherein the withdrawal of the corticosteroid treatment inthe patient is at about 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or 9weeks after the first administration.
 16. The method of claim 1, whereinthe administration of the interleukin-1 receptor-Fc fusion proteinresults in reduced risk of pericarditis recurrence of less than 5%.